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Sub-chronic administration of phencyclidine produces hypermethylation in the parvalbumin gene promoter in rat brainHelene A. Fachim1,*, Umarat Srisawat1, Caroline F. Dalton1, Michael K. Harte2, Samuel Marsh2, Joanna C. Neill 2, Gavin P. Reynolds1.1 Biomolecular Sciences Research Centre, Sheffield Hallam University, Sheffield S1 1WB, UK2 Manchester Pharmacy School, University of Manchester, Manchester M13 9PT, UK*Corresponding author.Current address: Department of Neuroscience and Behavior, Medical School of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil.hfachim@.br +5516981734400 AbstractAims: A deficit in parvalbumin (PV) neurons is found in schizophrenia and several animal models of the disease. In this preliminary study, we determined whether one such model, phencyclidine (PCP) administration, results in changes in DNA methylation in the rat PV gene (Pvalb) promoter. Methods: DNA from hippocampus and prefrontal cortex (PFC) from rats, which 6 weeks previously received either 2mg/kg PCP or vehicle for 7 days, underwent bisulphite pyrosequencing to determine methylation. Results: PCP administration induced significantly greater methylation at one of two Pvalb CpG sites in both PFC and hippocampus, while no significant difference was found in Long Interspersed Nucleotide Element-1, a global measure of DNA methylation. Conclusion: Subchronic PCP administration results in a specific hypermethylation in the Pvalb promoter which may contribute to PV deficits in this animal model of psychosis. Keywords: DNA methylation, parvalbumin, phencyclidine, schizophrenia, novel object recognition, rat.1. IntroductionThe NMDA receptor antagonist phencyclidine (PCP) has been widely used in the investigation and modelling of psychotic illness. Sub-chronic administration of PCP to animals can induce brain metabolic and neurochemical changes ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "Numerous human imaging studies have revealed an absolute or relative metabolic hypofunction within the prefrontal cortex, thalamus and temporal lobes of schizophrenic patients. The former deficit correlates with cognitive deficits and negative symptoms, whereas the latter correlates with positive symptomologies. There is also general consensus that schizophrenia is associated with decreased parvalbumin expression in the prefrontal cortex. Since the drug phencyclidine can induce a psychosis resembling schizophrenia in humans, we have examined whether repeated phencyclidine (PCP) treatment to rats could produce similar metabolic and neurochemical deficits to those occurring in schizophrenia and whether these deficits could be modulated by antipsychotic drugs. We demonstrate here that chronic intermittent exposure to PCP (2.58 mg kg(-1) i.p.) elicits a metabolic hypofunction, as demonstrated by reductions in the rates of glucose utilization, within the prefrontal cortex, reticular nucleus of thalamus and auditory system, key structures displaying similar changes in schizophrenia. Moreover, chronic PCP treatment according to this regime also decreases parvalbumin mRNA expression in the rat prefrontal cortex and reticular nucleus of the thalamus. Chronic coadministration of haloperidol (1 mg kg(-1) day(-1)) or clozapine (20 mg kg(-1) day(-1)) with PCP did not modulate PCP-induced reductions in metabolic activity in the rat prefrontal cortex, but reversed deficits in the structures of the auditory system. Clozapine, but not haloperidol, reversed PCP-induced decreases in parvalbumin expression in prefrontal cortex GABAergic interneurons, whereas both drugs reversed the deficits in the reticular nucleus of the thalamus. These data provide important new information, which strengthen the validity of chronic PCP as a useful animal model of schizophrenia, when administered according to this protocol. Furthermore, we propose that reversal of PCP-induced reductions in parvalbumin expression in the prefrontal cortex may be a potential marker of atypical antipsychotic activity in relation to amelioration of cognitive deficits and negative symptoms of schizophrenia.", "author" : [ { "dropping-particle" : "", "family" : "Cochran", "given" : "Susan M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kennedy", "given" : "Matthew", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McKerchar", "given" : "Clare E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Steward", "given" : "Lucinda J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pratt", "given" : "Judith A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Morris", "given" : "Brian J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2003" ] ] }, "page" : "265-275", "title" : "Induction of metabolic hypofunction and neurochemical deficits after chronic intermittent exposure to phencyclidine: differential modulation by antipsychotic drugs.", "type" : "article-journal", "volume" : "28" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[1]", "plainTextFormattedCitation" : "[1]", "previouslyFormattedCitation" : "[1]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[1] as well as behaviours ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "Acute administration of the psychotomimetic phencyclidine (PCP) can mimic some features of schizophrenia, while a repeated treatment regimen of PCP may provide a more effective way to model in animals the enduring cognitive dysfunction observed in many schizophrenic patients. The present study aims to investigate behavioural and neuropathological effects of sub-chronic PCP administration. The cognitive deficit induced by sub-chronic PCP was examined using a previously established operant reversal-learning paradigm. Subsequently, the effect of sub-chronic PCP on parvalbumin-immunoreactive (parvalbumin-IR) neurons was assessed using immunohistochemical techniques. Rats were trained to respond for food in an operant reversal-learning paradigm for approximately 6 weeks, followed by sub-chronic administration of PCP (2mg/kg) or vehicle twice daily for 7 days followed 7 days later by behavioural testing. Six weeks post PCP, brains were analysed using immunohistochemical techniques to determine the size and density of parvalbumin-IR in the frontal cortex and hippocampus. Sub-chronic PCP significantly reduced (p <0.001) percentage correct responding in the reversal phase relative to the initial phase, an effect that persisted throughout the experimental period (4 weeks). The density of parvalbumin-IR neurons was reduced in the hippocampus, with significant reductions in the dentate gyrus and CA2/3 regions (p <0.001). There were significant changes in the frontal cortex, with a reduction (p <0.01) in the M1 (motor area 1) region and increases in the M2 (motor area 2) region and cingulate cortex (p <0.01-p <0.001). These results parallel findings of profound hippocampal and more subtle cortical deficits of parvalbumin-IR neurons in schizophrenia, and provide evidence to suggest that sub-chronic PCP can induce a lasting cognitive deficit, an effect that may be related to the observed neuronal deficits.", "author" : [ { "dropping-particle" : "", "family" : "Abdul-Monim", "given" : "Z", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Neill", "given" : "J C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Reynolds", "given" : "G P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of psychopharmacology (Oxford, England)", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2007" ] ] }, "page" : "198-205", "title" : "Sub-chronic psychotomimetic phencyclidine induces deficits in reversal learning and alterations in parvalbumin-immunoreactive expression in the rat.", "type" : "article-journal", "volume" : "21" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[2]", "plainTextFormattedCitation" : "[2]", "previouslyFormattedCitation" : "[2]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[2] that mimic aspects of schizophrenia. Furthermore, this regime can also produce enduring deficits in several neurochemical markers that are also diminished in the brain in schizophrenia. These include the calcium binding protein parvalbumin (PV), which is expressed in a subgroup of GABAergic neurons, and in schizophrenia demonstrates reductions in frontal cortical regions ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "Recent studies have provided evidence for a functional impairment of ??-aminobutyric acid (GABA)-containing interneurons in the prefrontal cortex of schizophrenics. This evidence includes reported deficits of basket and chandelier cells, which are known to contain the calcium-binding protein parvalbumin. Using a monoclonal antibody against parvalbumin we investigated possible changes in this subpopulation of neurons in the prefrontal cortex of schizophrenic cases and controls. Significantly reduced numbers of parvalbumin-immunoreactive neurons were observed in laminae III and IV, while no difference was detected in cortical width. Our findings are consistent with damage following a toxic insult, occurring during a developmental 'window of vulnerability' and specifically affecting this subpopulation of GABAergic neurons.", "author" : [ { "dropping-particle" : "", "family" : "Beasley", "given" : "Clare L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Reynolds", "given" : "Gavin P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Schizophrenia Research", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "1997" ] ] }, "page" : "349-355", "title" : "Parvalbumin-immunoreactive neurons are reduced in the prefrontal cortex of schizophrenics", "type" : "article-journal", "volume" : "24" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "abstract" : "Research aimed at understanding the neurotransmitter pathology of schizophrenia has been underway for half a century, with much emphasis on the dopamine system. Although this approach has advanced our understanding of treatment mechanisms, identification of primary dopaminergic abnormalities in the disease has been elusive. The increasing emphasis on a neuronal pathology of schizophrenia has led to the identification of abnormalities in GABAergic and glutamatergic systems; and we have identified selective deficits in GABAergic interneurons containing the calcium binding proteins parvalbumin and calbindin. Here we report further evidence for a loss of parvalbumin-immunoreactive neurons in both dorsolateral prefrontal and medial temporal cortex, indicating that these deficits are consistent with a subtle neurodevelopmental pathogenesis and hypothesizing that they may contribute to a further degenerative process in schizophrenia.", "author" : [ { "dropping-particle" : "", "family" : "Reynolds", "given" : "G. P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Beasley", "given" : "C. L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhang", "given" : "Z. J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of Neural Transmission", "id" : "ITEM-2", "issue" : "5-6", "issued" : { "date-parts" : [ [ "2002" ] ] }, "page" : "881-889", "title" : "Understanding the neurotransmitter pathology of schizophrenia: Selective deficits of subtypes of cortical GABAergic neurons", "type" : "article-journal", "volume" : "109" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[3,4]", "plainTextFormattedCitation" : "[3,4]", "previouslyFormattedCitation" : "[3,4]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[3] and, particularly profoundly, in the hippocampus ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "Research aimed at understanding the neurotransmitter pathology of schizophrenia has been underway for half a century, with much emphasis on the dopamine system. Although this approach has advanced our understanding of treatment mechanisms, identification of primary dopaminergic abnormalities in the disease has been elusive. The increasing emphasis on a neuronal pathology of schizophrenia has led to the identification of abnormalities in GABAergic and glutamatergic systems; and we have identified selective deficits in GABAergic interneurons containing the calcium binding proteins parvalbumin and calbindin. Here we report further evidence for a loss of parvalbumin-immunoreactive neurons in both dorsolateral prefrontal and medial temporal cortex, indicating that these deficits are consistent with a subtle neurodevelopmental pathogenesis and hypothesizing that they may contribute to a further degenerative process in schizophrenia.", "author" : [ { "dropping-particle" : "", "family" : "Reynolds", "given" : "G. P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Beasley", "given" : "C. L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhang", "given" : "Z. J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of Neural Transmission", "id" : "ITEM-1", "issue" : "5-6", "issued" : { "date-parts" : [ [ "2002" ] ] }, "page" : "881-889", "title" : "Understanding the neurotransmitter pathology of schizophrenia: Selective deficits of subtypes of cortical GABAergic neurons", "type" : "article-journal", "volume" : "109" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[4]", "plainTextFormattedCitation" : "[4]", "previouslyFormattedCitation" : "[4]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[4]. Equivalent losses, typically greater than 50%, of PV-immunoreactive (PV-IR) cells, are also seen in the rat hippocampus following sub-chronic PCP ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "Acute administration of the psychotomimetic phencyclidine (PCP) can mimic some features of schizophrenia, while a repeated treatment regimen of PCP may provide a more effective way to model in animals the enduring cognitive dysfunction observed in many schizophrenic patients. The present study aims to investigate behavioural and neuropathological effects of sub-chronic PCP administration. The cognitive deficit induced by sub-chronic PCP was examined using a previously established operant reversal-learning paradigm. Subsequently, the effect of sub-chronic PCP on parvalbumin-immunoreactive (parvalbumin-IR) neurons was assessed using immunohistochemical techniques. Rats were trained to respond for food in an operant reversal-learning paradigm for approximately 6 weeks, followed by sub-chronic administration of PCP (2mg/kg) or vehicle twice daily for 7 days followed 7 days later by behavioural testing. Six weeks post PCP, brains were analysed using immunohistochemical techniques to determine the size and density of parvalbumin-IR in the frontal cortex and hippocampus. Sub-chronic PCP significantly reduced (p <0.001) percentage correct responding in the reversal phase relative to the initial phase, an effect that persisted throughout the experimental period (4 weeks). The density of parvalbumin-IR neurons was reduced in the hippocampus, with significant reductions in the dentate gyrus and CA2/3 regions (p <0.001). There were significant changes in the frontal cortex, with a reduction (p <0.01) in the M1 (motor area 1) region and increases in the M2 (motor area 2) region and cingulate cortex (p <0.01-p <0.001). These results parallel findings of profound hippocampal and more subtle cortical deficits of parvalbumin-IR neurons in schizophrenia, and provide evidence to suggest that sub-chronic PCP can induce a lasting cognitive deficit, an effect that may be related to the observed neuronal deficits.", "author" : [ { "dropping-particle" : "", "family" : "Abdul-Monim", "given" : "Z", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Neill", "given" : "J C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Reynolds", "given" : "G P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of psychopharmacology (Oxford, England)", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2007" ] ] }, "page" : "198-205", "title" : "Sub-chronic psychotomimetic phencyclidine induces deficits in reversal learning and alterations in parvalbumin-immunoreactive expression in the rat.", "type" : "article-journal", "volume" : "21" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[2]", "plainTextFormattedCitation" : "[2]", "previouslyFormattedCitation" : "[2]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[2].Deficits in immunostaining for PV-positive neurons have also been seen in other animal models that mimic some of the behavioural and also, in some models, the aetiological characteristics of schizophrenia. These include isolation rearing ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1007/s00702-007-0627-6", "ISSN" : "1435-1463", "PMID" : "17594127", "abstract" : "Post-mortem studies have provided evidence for abnormalities of the gamma-aminobutyric acid (GABA)-ergic system in schizophrenia. The calcium-binding proteins (CBPs), parvalbumin (PV), calbindin (CB) and calretinin (CR) can be used as markers for specific subpopulations of GABAergic neurons in the brain. Isolation rearing of rats is a non-pharmacological, non-lesion manipulation that leads to deficits in prepulse inhibition of the startle reflex (PPI) and other behavioural and neurochemical alterations reminiscent of schizophrenia. Female rats were reared in social housing (groups of three) or singly for 11 weeks post weaning and PPI was measured. Brains were removed and hippocampal CBP- containing neurons determined following immunocytochemical staining. Compared to socially housed rats, isolated rats exhibited PPI deficits and reductions in PV and CB-immunoreactive cells in the hippocampus, with no significant change in CR. These findings demonstrate selective abnormalities of sub-populations of GABAergic interneurons in the hippocampus of isolation reared rats, which resemble the neuronal deficits seen in this region in schizophrenia.", "author" : [ { "dropping-particle" : "", "family" : "Harte", "given" : "M K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Powell", "given" : "S B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Swerdlow", "given" : "N R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Geyer", "given" : "M A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Reynolds", "given" : "G P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of neural transmission (Vienna, Austria : 1996)", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2007", "7" ] ] }, "page" : "893-8", "title" : "Deficits in parvalbumin and calbindin immunoreactive cells in the hippocampus of isolation reared rats.", "type" : "article-journal", "volume" : "114" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[5]", "plainTextFormattedCitation" : "[5]", "previouslyFormattedCitation" : "[5]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[5], administration of neonatal endotoxin ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "Early exposure to infection is known to affect brain development and has been linked to an increased risk for schizophrenia. The present study aimed to determine whether neonatal infection produced long-term disruptions in behaviour and pathology that might provide a parallel with that observed in schizophrenia. Rats were administered lipopolysaccharide (LPS; 500 \u03bcg/kg i.p.) on postnatal day 7 and 9. Locomotor activity and object recognition memory were tested at day 35 and day 70. LPS animals were observed to be less active at adulthood as measured by locomotor activity. With regards to object recognition memory, LPS administration produced no early impairment in task performance, however, at day 70 LPS animals spent significantly less time exploring the novel object than control animals. Analysis of brains showed a reduction in expression of parvalbumin immunoreactive neurons in the hippocampus of LPS animals with significant reductions selectively localised to the CA1-CA3 region, and not the dentate gyrus. No changes were observed in prefrontal cortex. These results show that neonatal LPS results in pathophysiological brain changes in hippocampal CA1-CA3 subregions. \u00a9 2009 Elsevier B.V. All rights reserved.", "author" : [ { "dropping-particle" : "", "family" : "Jenkins", "given" : "Trisha A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Harte", "given" : "Michael K.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stenson", "given" : "Gillian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Reynolds", "given" : "Gavin P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Behavioural Brain Research", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2009" ] ] }, "page" : "355-359", "title" : "Neonatal lipopolysaccharide induces pathological changes in parvalbumin immunoreactivity in the hippocampus of the rat", "type" : "article-journal", "volume" : "205" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[6]", "plainTextFormattedCitation" : "[6]", "previouslyFormattedCitation" : "[6]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[6] and prenatal methylazoxymethanol (MAM) ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/j.1460-9568.2005.04536.x", "ISSN" : "0953-816X", "PMID" : "16420437", "abstract" : "Treatment of rats with methylazoxymethanol (MAM) on gestational day (GD)17 disrupts corticolimbic development in the offspring (MAM-GD17 rats) and leads to abnormalities in adult MAM-GD17 rats resembling those described in schizophrenic patients. The underlying changes in specific cortical and limbic cell populations remain to be characterised. In schizophrenia, decreases in inhibitory gamma-aminobutyric acid (GABA)-containing interneurons that express the calcium-binding protein parvalbumin have been reported in the prefrontal cortex and hippocampus. In this study we analysed the expression of parvalbumin (PV), calretinin (CR) and calbindin (CB) in the prefrontal cortex and hippocampus of MAM-GD17 rats. Exposure in utero to MAM led to a significant decrease in the number of neurons expressing PV in the hippocampus, but not the prefrontal cortex. Neurons expressing CR or CB were not affected in either structure. The neurochemical changes in MAM-GD17 rats were accompagnied by increased hyperlocomotion after administration of phencyclidine (PCP), analogous to the hypersensitivity of schizophrenic patients to PCP. Therefore, the developmental MAM-GD17 model reproduces key neurochemical and behavioural features that reflect cortical and subcortical dysfunction in schizophrenia, and could be a useful tool in the development of new antipsychotic drugs.", "author" : [ { "dropping-particle" : "", "family" : "Penschuck", "given" : "Silke", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Flagstad", "given" : "Peter", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Didriksen", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Leist", "given" : "Marcel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Michael-Titus", "given" : "Adina T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The European journal of neuroscience", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2006", "1" ] ] }, "page" : "279-84", "title" : "Decrease in parvalbumin-expressing neurons in the hippocampus and increased phencyclidine-induced locomotor activity in the rat methylazoxymethanol (MAM) model of schizophrenia.", "type" : "article-journal", "volume" : "23" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[7]", "plainTextFormattedCitation" : "[7]", "previouslyFormattedCitation" : "[7]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[7] in rats, as well as following other psychotogenic drugs including ketamine ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1126/science.1148045", "ISSN" : "1095-9203", "PMID" : "18063801", "abstract" : "Abuse of the dissociative anesthetic ketamine can lead to a syndrome indistinguishable from schizophrenia. In animals, repetitive exposure to this N-methyl-d-aspartate-receptor antagonist induces the dysfunction of a subset of cortical fast-spiking inhibitory interneurons, with loss of expression of parvalbumin and the gamma-aminobutyric acid-producing enzyme GAD67. We show here that exposure of mice to ketamine induced a persistent increase in brain superoxide due to activation in neurons of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Decreasing superoxide production prevented the effects of ketamine on inhibitory interneurons in the prefrontal cortex. These results suggest that NADPH oxidase may represent a novel target for the treatment of ketamine-induced psychosis.", "author" : [ { "dropping-particle" : "", "family" : "Behrens", "given" : "M Margarita", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ali", "given" : "Sameh S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dao", "given" : "Diep N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lucero", "given" : "Jacinta", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shekhtman", "given" : "Grigoriy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Quick", "given" : "Kevin L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dugan", "given" : "Laura L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Science (New York, N.Y.)", "id" : "ITEM-1", "issue" : "5856", "issued" : { "date-parts" : [ [ "2007", "12", "7" ] ] }, "page" : "1645-7", "title" : "Ketamine-induced loss of phenotype of fast-spiking interneurons is mediated by NADPH-oxidase.", "type" : "article-journal", "volume" : "318" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "abstract" : "The underlying mechanisms of schizophrenia pathogenesis are not well understood. Increasing evidence supports the glutamatergic hypothesis that posits a hypofunction of the N-methyl d-aspartate (NMDA) receptor on specific gamma amino-butyric acid (GABA)-ergic neurons may be responsible for the disorder. Alterations in the GABAergic system have been observed in schizophrenia, most notably a change in the expression of parvalbumin (PV) in the cortex and hippocampus. Several reports also suggest abnormal neuronal migration may play a role in the etiology of schizophrenia. The current study examined the positioning and distribution of PV-positive cells in the hippocampus following chronic treatment with the NMDA receptor antagonist ketamine. A robust increase was found in the number of PV-positive interneurons located outside the stratum oriens (SO), the layer where most of these cells are normally localized, as well as an overall numerical increase in CA3 PV cells. These results suggest ketamine leads to an abnormal distribution of PV-positive cells, which may be indicative of aberrant migratory activity and possibly related to the Morris water maze deficits observed. These findings may also be relevant to alterations observed in schizophrenia populations. \u00a9 2013 Elsevier Ireland Ltd.", "author" : [ { "dropping-particle" : "", "family" : "Sabbagh", "given" : "Jonathan J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Murtishaw", "given" : "Andrew S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bolton", "given" : "Monica M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Heaney", "given" : "Chelcie F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Langhardt", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kinney", "given" : "Jefferson W.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neuroscience Letters", "id" : "ITEM-2", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "69-74", "title" : "Chronic ketamine produces altered distribution of parvalbumin-positive cells in the hippocampus of adult rats", "type" : "article-journal", "volume" : "550" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[8,9]", "plainTextFormattedCitation" : "[8,9]", "previouslyFormattedCitation" : "[8,9]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[8,9] and amphetamine ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "The increase in excitatory outflow from the medial prefrontal cortex is critical to the development of sensitization to amphetamine. There is evidence that psychostimulant-induced changes in dopamine-GABA interactions are key to understanding the behaviorally sensitized response. The objective of this study was to characterize the effects of different amphetamine paradigms on the Fos activation of GABAergic interneurons that contain parvalbumin in the medial prefrontal cortex. Although a sensitizing, repeated regimen of amphetamine induced Fos in all cortical layers, only layer V parvalbumin-immunolabeled cells were activated in the infralimbic and prelimbic cortices. Repeated amphetamine treatment was also associated with a loss of parvalbumin immunoreactivity in layer V, but only in the prelimbic cortex. An acute amphetamine injection to naive rats was associated with an increase in Fos, but in parvalbumin-positive neurons of the prelimbic cortex, where it was preferentially induced in layer III. These data indicate that distinct substrates mediate the response to repeated or acute amphetamine treatment. They also suggest that a sensitizing amphetamine regimen directs medial prefrontal cortex (mPFC) outflow, via changes in inhibitory neuron activation, toward subcortical centers important in reward. ?? 2007 IBRO.", "author" : [ { "dropping-particle" : "", "family" : "Morshedi", "given" : "M. M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Meredith", "given" : "Gloria E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neuroscience", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2007" ] ] }, "page" : "617-624", "title" : "Differential laminar effects of amphetamine on prefrontal parvalbumin interneurons", "type" : "article-journal", "volume" : "149" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[10]", "plainTextFormattedCitation" : "[10]", "previouslyFormattedCitation" : "[10]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[10]. The pathogenic mechanisms underlying these deficits in PV are unclear, although PCP can also induce decreases in PV gene (Pvalb) expression ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "Numerous human imaging studies have revealed an absolute or relative metabolic hypofunction within the prefrontal cortex, thalamus and temporal lobes of schizophrenic patients. The former deficit correlates with cognitive deficits and negative symptoms, whereas the latter correlates with positive symptomologies. There is also general consensus that schizophrenia is associated with decreased parvalbumin expression in the prefrontal cortex. Since the drug phencyclidine can induce a psychosis resembling schizophrenia in humans, we have examined whether repeated phencyclidine (PCP) treatment to rats could produce similar metabolic and neurochemical deficits to those occurring in schizophrenia and whether these deficits could be modulated by antipsychotic drugs. We demonstrate here that chronic intermittent exposure to PCP (2.58 mg kg(-1) i.p.) elicits a metabolic hypofunction, as demonstrated by reductions in the rates of glucose utilization, within the prefrontal cortex, reticular nucleus of thalamus and auditory system, key structures displaying similar changes in schizophrenia. Moreover, chronic PCP treatment according to this regime also decreases parvalbumin mRNA expression in the rat prefrontal cortex and reticular nucleus of the thalamus. Chronic coadministration of haloperidol (1 mg kg(-1) day(-1)) or clozapine (20 mg kg(-1) day(-1)) with PCP did not modulate PCP-induced reductions in metabolic activity in the rat prefrontal cortex, but reversed deficits in the structures of the auditory system. Clozapine, but not haloperidol, reversed PCP-induced decreases in parvalbumin expression in prefrontal cortex GABAergic interneurons, whereas both drugs reversed the deficits in the reticular nucleus of the thalamus. These data provide important new information, which strengthen the validity of chronic PCP as a useful animal model of schizophrenia, when administered according to this protocol. Furthermore, we propose that reversal of PCP-induced reductions in parvalbumin expression in the prefrontal cortex may be a potential marker of atypical antipsychotic activity in relation to amelioration of cognitive deficits and negative symptoms of schizophrenia.", "author" : [ { "dropping-particle" : "", "family" : "Cochran", "given" : "Susan M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kennedy", "given" : "Matthew", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McKerchar", "given" : "Clare E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Steward", "given" : "Lucinda J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pratt", "given" : "Judith A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Morris", "given" : "Brian J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2003" ] ] }, "page" : "265-275", "title" : "Induction of metabolic hypofunction and neurochemical deficits after chronic intermittent exposure to phencyclidine: differential modulation by antipsychotic drugs.", "type" : "article-journal", "volume" : "28" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "abstract" : "Current treatments of schizophrenia are compromised by their inability to treat all symptoms of the disease and their side-effects. Whilst existing antipsychotic drugs are effective against positive symptoms, they have negligible efficacy against the prefrontal cortex (PFC)-associated cognitive deficits and negative symptoms. New models that reproduce core pathophysiological features of schizophrenia are more likely to have improved predictive validity in identifying new treatments. We have developed a NMDA receptor antagonist model that reproduces core PFC deficits of schizophrenia and discuss this in relation to pathophysiology and treatments. Subchronic and chronic intermittent PCP (2.6 mg/kg i.p.) was administered to rats. PFC activity was assessed by 2-deoxyglucose imaging, parvalbumin and Kv3.1 mRNA expression, and the attentional set-shifting test (ASST) of executive function. Affymetrix gene array technology was employed to examine gene expression profile patterns. PCP treatment reduced glucose utilization in the PFC (hypofrontality). This was accompanied by a reduction in markers of GABAergic interneurones (parvalbumin and Kv3.1 mRNA expression) and deficits in the extradimensional shift dimension of the ASST. Consistent with their clinical profile, the hypofrontality was not reversed by clozapine or haloperidol. Transcriptional analysis revealed patterns of change consistent with current neurobiological theories of schizophrenia. This model mirrors core neurobiological deficits of schizophrenia; hypofrontality, altered markers of GABAergic interneurone activity and deficits in executive function. As such it is likely to be a valuable translational model for understanding the neurobiological mechanisms underlying hypofrontality and for identifying and validating novel drug targets that may restore PFC deficits in schizophrenia.", "author" : [ { "dropping-particle" : "", "family" : "Pratt", "given" : "J A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Winchester", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Egerton", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cochran", "given" : "S M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Morris", "given" : "B J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "British journal of pharmacology", "id" : "ITEM-2", "issued" : { "date-parts" : [ [ "2008" ] ] }, "page" : "S465-S470", "title" : "Modelling prefrontal cortex deficits in schizophrenia: implications for treatment.", "type" : "article-journal", "volume" : "153 Suppl " }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[1,11]", "plainTextFormattedCitation" : "[1,11]", "previouslyFormattedCitation" : "[1,11]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[1,11]. We have speculated whether the PV deficit might relate to epigenetic changes induced by such pharmacological and environmental influences. One epigenetic factor is that of DNA methylation occurring at cytosine residues in CpG sequences; within promoter sequences this methylation can have major effects on gene expression ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/npp.2012.125", "ISSN" : "1740-634X", "PMID" : "22948975", "abstract" : "Major psychiatric disorders such as schizophrenia (SZ) and bipolar disorder (BP) with psychosis (BP+) express a complex symptomatology characterized by positive symptoms, negative symptoms, and cognitive impairment. Postmortem studies of human SZ and BP+ brains show considerable alterations in the transcriptome of a variety of cortical structures, including multiple mRNAs that are downregulated in both inhibitory GABAergic and excitatory pyramidal neurons compared with non-psychiatric subjects (NPS). Several reports show increased expression of DNA methyltransferases in telencephalic GABAergic neurons. Accumulating evidence suggests a critical role for altered DNA methylation processes in the pathogenesis of SZ and related psychiatric disorders. The establishment and maintenance of CpG site methylation is essential during central nervous system differentiation and this methylation has been implicated in synaptic plasticity, learning, and memory. Atypical hypermethylation of candidate gene promoters expressed in GABAergic neurons is associated with transcriptional downregulation of the corresponding mRNAs, including glutamic acid decarboxylase 67 (GAD67) and reelin (RELN). Recent reports indicate that the methylation status of promoter proximal CpG dinucleotides is in a dynamic balance between DNA methylation and DNA hydroxymethylation. Hydroxymethylation and subsequent DNA demethylation is more complex and involves additional proteins downstream of 5-hydroxymethylcytosine, including members of the base excision repair (BER) pathway. Recent advances in our understanding of altered CpG methylation, hydroxymethylation, and active DNA demethylation provide a framework for the identification of new targets, which may be exploited for the pharmacological intervention of the psychosis associated with SZ and possibly BP+.", "author" : [ { "dropping-particle" : "", "family" : "Grayson", "given" : "Dennis R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Guidotti", "given" : "Alessandro", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "138-66", "publisher" : "Nature Publishing Group", "title" : "The dynamics of DNA methylation in schizophrenia and related psychiatric disorders.", "type" : "article-journal", "volume" : "38" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[12]", "plainTextFormattedCitation" : "[12]", "previouslyFormattedCitation" : "[12]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[12]. There is evidence for dynamic effects on methylation of the mouse PV gene promoter sequence associated with manganese-induced neurotoxic damage ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "We have shown that maternal manganese (Mn) exposure caused sustained disruption of hippocampal neurogenesis of mouse offspring. To clarify the effects of maternal Mn exposure on epigenetic gene regulation contributing to the sustained disruption of hippocampal neurogenesis, we treated pregnant ICR mice with MnCl\u2082 in diet from gestational day 10 through day 21 after delivery on weaning and searched epigenetically downregulated genes by global promoter methylation analysis in the hippocampal dentate gyrus of male offspring on postnatal day (PND) 21 and PND 77. By CpG promoter microarray analysis on PND 21 following 800-ppm Mn exposure, sustained promoter hypermethylation and transcript downregulation through PND 77 were confirmed with Mid1, Atp1a3, and Nr2f1, whereas Pvalb showed a transient hypermethylation only on weaning. The numbers of Pvalb\u207a and ATP1a3\u207a neurons suggestive of \u03b3-aminobutyric acid (GABA)ergic interneurons, Mid1\u207a cells suggestive of late-stage granule cell lineage and GABAergic interneurons, and COUP-TF1\u207a cells suggestive of early-stage granule cell lineage were all reduced on PND 21, and reductions were sustained on PND 77 except for no change in Pvalb\u207a cells. Mid1\u207a cells showed asymmetric distribution with right-side predominance, and Mn exposure abolished it by promoter hypermethylation of the right side. These findings indicate epigenetic mechanisms as mediators, through which Mn exposure modulates neurogenesis involving both granule cell lineage and GABAergic interneurons with long-lasting and stable repercussions. Disruption of asymmetric cellular distribution of Mid1 suggests that higher brain functions specialized in the left or right side of the brain were affected.", "author" : [ { "dropping-particle" : "", "family" : "Wang", "given" : "Liyun", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shiraki", "given" : "Ayako", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Itahashi", "given" : "Megu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Akane", "given" : "Hirotoshi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Abe", "given" : "Hajime", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mitsumori", "given" : "Kunitoshi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shibutani", "given" : "Makoto", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Toxicological Sciences", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "154-165", "title" : "Aberration in epigenetic gene regulation in hippocampal neurogenesis by developmental exposure to manganese chloride in mice", "type" : "article-journal", "volume" : "136" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[13]", "plainTextFormattedCitation" : "[13]", "previouslyFormattedCitation" : "[13]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[13]; we hypothesised that changes in methylation of this sequence might relate to PV deficits in schizophrenia and its animal models. In this preliminary study we have determined the methylation status of CpG methylation sites within the equivalent sequence in frontal cortical (PFC) and hippocampal tissue from rats that had received subchronic PCP. The results were compared with a global measure of DNA methylation, that of Long Interspersed Nucleotide Element-1 (LINE-1) ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "Long interspersed element-1 (LINE-1 or L1) is a repetitive DNA retrotransposon capable of duplication by a copy-and-paste genetic mechanism. Scattered throughout mammalian genomes, L1 is typically quiescent in most somatic cell types. In developing neurons, however, L1 can express and retrotranspose at high frequency. The L1 element can insert into various genomic locations including intragenic regions. These insertions can alter the dynamic of the neuronal transcriptome by changing the expression pattern of several nearby genes. The consequences of L1 genomic alterations in somatic cells are still under investigation, but the high level of mutagenesis within neurons suggests that each neuron is genetically unique. Furthermore, some neurological diseases, such as Rett syndrome and ataxia telangiectasia, misregulate L1 retrotransposition, which could contribute to some pathological aspects. In this review, we survey the literature related to neurodevelopmental retrotransposition and discuss possible relevance to neuronal function, evolution, and neurological disease.", "author" : [ { "dropping-particle" : "", "family" : "Thomas", "given" : "Charles A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Paquola", "given" : "Apu\u00e3 C.M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Muotri", "given" : "Alysson R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Annual Review of Cell and Developmental Biology", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2012" ] ] }, "page" : "555-573", "title" : "LINE-1 Retrotransposition in the Nervous System", "type" : "article", "volume" : "28" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "abstract" : "Long interspersed elements type 1 (LINE-1s, or L1s) have impacted mammalian genomes at multiple levels. L1 transcription is mainly controlled by its 5' untranslated region (5'UTR), which differs significantly among active human and rodent L1 families. In this review, L1 expression and its regulation are examined in the context of human and rodent development. First, endogenous L1 expression patterns in three different species'human, rat, and mouse'are compared and contrasted. A detailed account of relevant experimental evidence is presented according to the source material, such as cell lines, tumors, and normal somatic and germline tissues from different developmental stages. Second, factors involved in the regulation of L1 expression at both transcriptional and posttranscriptional levels are discussed. These include transcription factors, DNA methylation, PIWIinteracting RNAs (piRNAs), RNA interference (RNAi), and posttranscriptional host factors. Similarities and differences between human and rodent L1s are highlighted. Third, recent findings from transgenic mouse models of L1 are summarized and contrasted with those from endogenous L1 studies. Finally, the challenges and opportunities for L1 mouse models are discussed.", "author" : [ { "dropping-particle" : "", "family" : "Rosser", "given" : "James, M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Frontiers in Bioscience", "id" : "ITEM-2", "issue" : "1", "issued" : { "date-parts" : [ [ "2012" ] ] }, "page" : "2203", "title" : "L1 expression and regulation in humans and rodents", "type" : "article", "volume" : "E4" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[14,15]", "plainTextFormattedCitation" : "[14,15]", "previouslyFormattedCitation" : "[14,15]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[14,15]. We used the novel object recognition (NOR) paradigm to assess the efficacy of the treatment regime to induce cognitive deficits prior to the post-mortem analysis.2. Material and MethodsFemale Lister-hooded rats (200-230g) were housed in groups of 4-5 under standard laboratory conditions under a 12hr light: dark cycle, lights on at 0700hr. Rats were randomly assigned to two groups and either received vehicle, (distilled water, i.p.) or phencyclidine hydrochloride (PCP, 2 mg/kg, i.p. twice daily for 7-days) dissolved in distilled water. Behavioural testing was carried out in the light phase. Rats were tested in the novel object recognition (NOR) paradigm and for locomotor activity 6 weeks after the last dose of PCP. Following the behavioural testing the brains were removed, flash frozen in isopentane and stored at -70%. These studies were carried out in accordance with the Animals Scientific Procedures Act (UK, 1986) and were approved by the University of Manchester ethical review panel.The NOR paradigm has been described in detail elsewhere ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.bbr.2007.06.012", "ISSN" : "0166-4328", "PMID" : "17675172", "abstract" : "The novel object recognition (NOR) task is a paradigm employed to detect both disruption and improvement of non-spatial memory in rats. PCP (phencyclidine) may be used to model aspects of schizophrenia symptomology in rats, in particular cognitive deficits. The aim of this study was to investigate the ability of typical and atypical antipsychotics to improve a sub-chronic PCP-induced impairment in cognition using the NOR task. Female hooded-Lister rats (195+/-12 g) received either vehicle (0.9% saline twice daily) or PCP (2 mg/kg, twice daily) for 7 days followed by 7-days drug free. Haloperidol (0.05 and 0.075 mg/kg), clozapine (1 and 5mg/kg), risperidone (0.05, 0.1 and 0.2 mg/kg) or vehicle (veh, saline) was administered i.p. 30 min prior to testing. Rats completed an acquisition trial followed by an inter-trial interval of 1 min, then a retention trial. Following sub-chronic vehicle treatment, rats spent significantly (p<0.05) more time exploring the novel compared to the familiar object, an effect that was abolished in the sub-chronic PCP treated animals. Clozapine (1.0 and 5.0 mg/kg) and risperidone (0.2 mg/kg) but not haloperidol significantly attenuated the PCP-induced impairment such that animals again spent significantly more time exploring the novel compared with familiar object (p<0.05). These results support our earlier work showing that acute PCP induces a robust object recognition deficit in female rats. Clozapine and risperidone but not haloperidol showed efficacy to reverse the deficit induced by sub-chronic PCP suggesting that this test may have some validity for assessing efficacy for improvement of cognitive deficit symptoms of schizophrenia.", "author" : [ { "dropping-particle" : "", "family" : "Grayson", "given" : "B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Idris", "given" : "N F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Neill", "given" : "J C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Behavioural brain research", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2007", "11", "22" ] ] }, "page" : "31-8", "title" : "Atypical antipsychotics attenuate a sub-chronic PCP-induced cognitive deficit in the novel object recognition task in the rat.", "type" : "article-journal", "volume" : "184" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[16]", "plainTextFormattedCitation" : "[16]", "previouslyFormattedCitation" : "[16]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[16]. Briefly, following habituation to the test box, the rats are given an initial acquisition trial during which the animals are allowed to explore two identical objects for 3 min. After a 1 min interval when the animals are removed, one object is replaced with a novel object and the animals allowed to explore the objects again for 3 min. The exploration times of each object in each trial are recorded on video for subsequent blind scoring. NOR was determined by the discrimination index (DI) in the retention trial, calculated as: (tn – tf) / (tn + tf) where tn and tf are times spent exploring the novel and familiar objects respectively. Data are expressed as mean ± SEM. (n= 9 per group) and were analysed by a one way ANOVA. Genomic DNA was extracted from PFC and hippocampal tissue using QIAamp DNA Blood Mini Kit (Qiagen, Valencia, CA), was bisulphite-modified to convert unmethylated cytosine residues to uracil using the EpiTec Fast DNA Bisulphite Kit (Qiagen) with a calculated mean conversion of 99%. We identified a previously-studied [13] DNA sequence in the 5’ region of the rat Pvalb gene (Rnor6.0, Chromosome 7, bases 119441848 - 119441803) that contained likely transcription factor binding sequences, and developed a pyrosequencing method for determination of methylation at the Pvalb CpG sites within this sequence following bisulphite reaction. The region containing the sequence of interest in the Pvalb promoter was amplified to yield an amplicon of 149 bases using primers: 5'-TAAGGGGTTTTATTGGGGTAGA-3' (forward) and 5'[btn]-ATCTAAAATACCACCAACAAACACTA-3' (reverse) (Eurofins MWG Operon). For LINE-1, a sequence of 4 CpGs was amplified ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "Tamoxifen, a nonsteroidal anti-estrogen, is a potent genotoxic hepatocarcinogen in rats, with both tumor initiating and promoting properties. Recently it has been demonstrated that genotoxic carcinogens, in addition to exerting genotoxic effects, often cause epigenetic alterations and these induced epigenetic changes may play important mechanistic role in carcinogenesis. In the present study, we investigated the role of tamoxifen-induced epigenetic changes in hepatocarcinogenic process. The results of the study showed that exposure of female F344 rats to tamoxifen resulted in progressive loss of CpG methylation in regulatory sequences of long interspersed nucleotide elements (LINE-1) and prominent increase in expression of LINE-1 elements and c-myc proto-oncogene. The accumulation of tamoxifen-induced DNA lesions was accompanied by the decreased level of Rad51, Ku70, and DNA polymerase beta (Polbeta) proteins that play a crucial role in maintenance of genomic stability. Furthermore, feeding rats with tamoxifen-containing diet led to increased regenerative cell proliferation, as indicated by the increased level of Ki-67 and proliferating cell nuclear antigen (PCNA) proteins. These data indicate that exposure of animals to genotoxic hepatocarcinogen tamoxifen led to early phenotypical alterations in livers characterized by emergence of epigenetically reprogrammed cells with a specific cancer-related epigenetic phenotype prior to tumor formation.", "author" : [ { "dropping-particle" : "", "family" : "Tryndyak", "given" : "Volodymyr P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kovalchuk", "given" : "Olga", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Muskhelishvili", "given" : "Levan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Montgomery", "given" : "Beverly", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rodrigues-Juarez", "given" : "Rocio", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Melnyk", "given" : "Stepan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ross", "given" : "Sharon A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Beland", "given" : "Frederick A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pogribny", "given" : "Igor P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Molecular Carcinogenesis", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2007" ] ] }, "page" : "187-197", "title" : "Epigenetic reprogramming of liver cells in tamoxifen-induced rat hepatocarcinogenesis", "type" : "article-journal", "volume" : "46" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[17]", "plainTextFormattedCitation" : "[17]", "previouslyFormattedCitation" : "[17]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[17] by PCR primers, as follows: 5'-TTGTTGTAAGAAAGTTGTTTGGTGAGTT-3' (forward) and 5'[btn]-ACCTCAAAAATACCCACCTAACC -3' (reverse) (Eurofins MWG Operon). Mean values for methylation were calculated and used as a measure of global methylation. PCR reactions were carried out with 20 ng bisulphite-converted DNA using the PyroMark PCR kit in a final volume of 25 ?l containing 12.5 ?l 1x PyroMark PCR Master Mix, 2.5 ?l 1x CoralLoad Concentrate, 1 ?l of each primer in a final concentration of 0.05 ?M, 7 ?l RNase-free water. Amplification conditions were as follows: 95°C for 15 min, 45 cycles of 94°C for 30 s, 56°C for 30 s and 72°C for 30 s, finally, 72°C for 10 min. Methylation status of the Pvalb promoter sequence was determined with a PyroMark Q24 pyrosequencer (Qiagen UK) using 15–20 ?l PCR product and a sequencing primer, 5'- GTAGAGGTTGGTTAGTAT-3' (Eurofins MWG Operon). LINE-1 methylation was determined with a sequencing primer 5'- GGTGAGTTTGGGATA-3' (Eurofins MWG Operon). Pyrosequence setup and data reading were conducted by PyroMark Q24 2.0.6.20 software. Samples underwent PCR and pyrosequencing in duplicate; any inconsistencies between samples were resolved following further repetition. The extent of methylation at Pvalb CpG sites was analysed by repeated-measures ANOVA with region and treatment (PCP/vehicle) as factors; significant effects were further investigated by post-hoc t-test. 3. ResultsDuring the acquisition trial in the NOR paradigm both groups spent an equal time exploring the left and right objects. In the retention trial the vehicle-treated, but not PCP-treated, animals spent more time exploring the novel versus the familiar object resulting in a significant difference in the discrimination index (vehicle: 0.35±0.04 vs PCP: 0.08±0.04; t-test p<0.01). There was no significant difference in locomotor activity between the groups (data not shown). Brain DNA extracts gave consistent results for methylation at the two CpG sites in the Pvalb sequence of interest. Methylation status of the Pvalb promoter sequence was significantly different between the two treatment groups (F=14.82, p=0.001) and showed a significant interaction with CpG site (F=11.05, p=0.002) but did not significantly differ between or interact with brain region. These findings reflected significantly greater methylation in CpG2 from the hippocampus (t=2.778; p=0.015) and the PFC (t=2.635; p=0.022) in the PCP group, with mean increases of 16% and 21% respectively (Fig 1). Mean methylation in the LINE-1 sequence showed no statistically significant effect of drug group or region with results as follows for PFC (PCP: 73.59±5.01%; vehicle: 77.06±7.91%) and hippocampus (PCP: 77.90±2.86%; vehicle: 77.45±4.81%)4. DiscussionIn this preliminary study we have demonstrated a highly significant elevation in DNA methylation in one of two CpG sites in the promoter sequence of the PV gene in brain tissue taken from rats previously receiving a sub-chronic regime of PCP. It is well-established that such PCP administration can induce an enduring deficit of PV-IR neurons and a reduction in PV gene expression ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "Glutamatergic and GABAergic neurotransmitter systems exist in equilibrium to maintain \"normal\" brain function. Evidence is accumulating that disturbance of this equilibrium may be one of the key factors giving rise to schizophrenia. While there is widespread evidence that the psychotomimetic phencyclidine (PCP) induces schizophrenia-related symptoms, it is not clear how this dramatic effect is mediated. This study was designed to investigate acute and delayed effects of PCP on the mRNA expression of a range of markers of neuronal function associated with the glutamatergic and GABAergic systems within the rat brain. The mRNA levels of CaMKIIalpha, an enzyme which is located within the postsynaptic density and phosphorylates AMPA receptors, remained unaltered both 2 and 24 h posttreatment. Homer 1a, an immediate early gene associated with metabotropic glutamate receptors within the postsynaptic density, displayed region-specific differential changes within the prefrontal, primary auditory, and retrosplenial cortices 2 and 24 h posttreatment. Parvalbumin, a calcium-binding protein located within a subpopulation of GABAergic interneurones, displayed altered mRNA levels within the reticular nucleus of the thalamus at 2 and 24 h posttreatment and the substantia nigra pars reticulata 24 h posttreatment only. These phencyclidine-induced changes in mRNA expression were not accompanied by any changes in hsp-70 mRNA levels, a marker of NMDA antagonist-induced reversible neurotoxicity. These results indicate that the glutamatergic (group I metabotropic glutamate receptors) and GABAergic (parvalbumin-containing interneurones) neurotransmitter systems are differentially modulated in a region- and time-dependent manner by exposure to phencyclidine.", "author" : [ { "dropping-particle" : "", "family" : "Cochran", "given" : "Susan M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fujimura", "given" : "Masatake", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Morris", "given" : "Brian J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pratt", "given" : "Judith A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Synapse", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2002" ] ] }, "page" : "206-214", "title" : "Acute and delayed effects of phencyclidine upon mRNA levels of markers of glutamatergic and GABAergic neurotransmitter function in the rat brain", "type" : "article-journal", "volume" : "46" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[18]", "plainTextFormattedCitation" : "[18]", "previouslyFormattedCitation" : "[18]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[18], as well as producing cognitive deficits, demonstrated here by the reduction in NOR. The increase in Pvalb methylation is found not to reflect a general, global increase in DNA methylation, being seen in the absence of a significant change in LINE-1 methylation, and therefore appears to be a relatively gene-specific consequence of PCP administration. The specific increase seen is of a similar magnitude to changes seen in other schizophrenia-associated genes in both human ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1186/s13059-014-0495-y", "ISSN" : "1474-760X", "PMID" : "25418840", "abstract" : "An exciting recent study examining the methylation profile of human brain tissue implicates early-life epigenetic disruption in the neurodevelopmental origin of schizophrenia.", "author" : [ { "dropping-particle" : "", "family" : "Ryan", "given" : "Joanne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Saffery", "given" : "Richard", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Genome biology", "id" : "ITEM-1", "issue" : "10", "issued" : { "date-parts" : [ [ "2014", "1" ] ] }, "page" : "495", "title" : "Crucial timing in schizophrenia: role of DNA methylation in early neurodevelopment.", "type" : "article-journal", "volume" : "15" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[19]", "plainTextFormattedCitation" : "[19]", "previouslyFormattedCitation" : "[19]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[19] and rat brain tissue ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1073/pnas.1408355111", "ISSN" : "1091-6490", "PMID" : "25385582", "abstract" : "Early-life adversity increases the risk for psychopathology in later life. The underlying mechanism(s) is unknown, but epigenetic variation represents a plausible candidate. Early-life exposures can disrupt epigenetic programming in the brain, with lasting consequences for gene expression and behavior. This evidence is primarily derived from animal studies, with limited study in humans due to inaccessibility of the target brain tissue. In humans, although there is evidence for DNA methylation changes in the peripheral blood of psychiatric patients, a fundamental question remains as to whether epigenetic markers in the blood can predict epigenetic changes occurring in the brain. We used in utero bisphenol A (BPA) exposure as a model environmental exposure shown to disrupt neurodevelopment and exert long-term effects on behavior in animals and humans. We show that prenatal BPA induces lasting DNA methylation changes in the transcriptionally relevant region of the Bdnf gene in the hippocampus and blood of BALB/c mice and that these changes are consistent with BDNF changes in the cord blood of humans exposed to high maternal BPA levels in utero. Our data suggest that BDNF DNA methylation in the blood may be used as a predictor of brain BDNF DNA methylation and gene expression as well as behavioral vulnerability induced by early-life environmental exposure. Because BDNF expression and DNA methylation are altered in several psychiatric disorders that are associated with early-life adversity, including depression, schizophrenia, bipolar disorder, and autism, BDNF DNA methylation in the blood may represent a novel biomarker for the early detection of psychopathology.", "author" : [ { "dropping-particle" : "", "family" : "Kundakovic", "given" : "Marija", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gudsnuk", "given" : "Kathryn", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Herbstman", "given" : "Julie B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tang", "given" : "Deliang", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Perera", "given" : "Frederica P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Champagne", "given" : "Frances A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Proceedings of the National Academy of Sciences of the United States of America", "id" : "ITEM-1", "issue" : "22", "issued" : { "date-parts" : [ [ "2015", "6", "2" ] ] }, "page" : "6807-13", "title" : "DNA methylation of BDNF as a biomarker of early-life adversity.", "type" : "article-journal", "volume" : "112" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[20]", "plainTextFormattedCitation" : "[20]", "previouslyFormattedCitation" : "[20]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[20]. Generally, DNA methylation is inversely related to gene expression, as promoter sequence methylation could directly interfere with transcription factor binding sites and also indirectly cause gene silencing through methylated DNA binding proteins that recruit histone deacetylases, leading to chromatin condensation ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/561", "ISSN" : "1061-4036", "PMID" : "9620779", "abstract" : "CpG methylation in vertebrates correlates with alterations in chromatin structure and gene silencing. Differences in DNA-methylation status are associated with imprinting phenomena and carcinogenesis. In Xenopus laevis oocytes, DNA methylation dominantly silences transcription through the assembly of a repressive nucleosomal array. Methylated DNA assembled into chromatin binds the transcriptional repressor MeCP2 which cofractionates with Sin3 and histone deacetylase. Silencing conferred by MeCP2 and methylated DNA can be relieved by inhibition of histone deacetylase, facilitating the remodelling of chromatin and transcriptional activation. These results establish a direct causal relationship between DNA methylation-dependent transcriptional silencing and the modification of chromatin.", "author" : [ { "dropping-particle" : "", "family" : "Jones", "given" : "P L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Veenstra", "given" : "G J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wade", "given" : "P A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vermaak", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kass", "given" : "S U", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Landsberger", "given" : "N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Strouboulis", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wolffe", "given" : "A P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature genetics", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "1998", "6" ] ] }, "page" : "187-91", "title" : "Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription.", "type" : "article-journal", "volume" : "19" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[21]", "plainTextFormattedCitation" : "[21]", "previouslyFormattedCitation" : "[21]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[21].The promoter activity of the sequence we have studied has been demonstrated ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "The structure of the rat parvalbumin gene has been elucidated from analysis of six overlapping clones isolated from a rat lambda Charon 4A genomic library. Two of the clones were mapped in detail, and all exons were localized by Southern hybridization using fragments of a full-length parvalbumin cDNA (Epstein, P., Means, A. R., and Berchtold, M. W. (1986) J. Biol. Chem. 261, 5886-5891). The rat parvalbumin transcription unit is 15.5 kilobase pairs in length and contains four introns. The first intron divides the 5'-nontranslated region, whereas the other three interrupt coding DNA. All intron/extron boundaries were sequenced as was 377 base pairs immediately 5' from the putative transcription initiation site. The promoter region contains eukaryotic regulatory homologies to the \"TATA\" box at -24 and \"CAAT\" box at -47 and -156. In addition, two doublets consisting of 11-base pair direct repeats exist in the promoter region. Parvalbumin binds two Ca2+, whereas many other members of the same superfamily bind four. Comparison of the genes that encode these proteins provides a strong confirmation of the hypothesis that parvalbumin evolved from an ancestral gene specifying a four-domain Ca2+-binding protein. The rat parvalbumin gene was also utilized to assign its human counterpart to chromosome 22 from data obtained by hybridization to DNA from a somatic cell hybrid panel. It was also used to isolate a 7.5-kilobase pair EcoRI fragment from a human chromosome 22 DNA library.", "author" : [ { "dropping-particle" : "", "family" : "Berchtold", "given" : "M. W.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Epstein", "given" : "P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Beaudet", "given" : "A. L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Payne", "given" : "M. E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Heizmann", "given" : "C. W.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Means", "given" : "A. R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of Biological Chemistry", "id" : "ITEM-1", "issue" : "18", "issued" : { "date-parts" : [ [ "1987" ] ] }, "page" : "8696-8701", "title" : "Structural organization and chromosomal assignment of the parvalbumin gene.", "type" : "article-journal", "volume" : "262" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "ISSN" : "0022-2836", "PMID" : "2614829", "abstract" : "The structural organization of the chromosomal gene for human parvalbumin was determined mostly by sequencing exons and intron exon junctions of a 7500 base-pair (bp) long genomic clone derived from a chromosome 22-specific gene library. Four exons coding for 100 from a total of 109 amino acids were detected in this clone and 472 bp of the 5'-flanking region were sequenced. The region corresponding to the C-terminal amino acids 101 to 109 of human parvalbumin was determined by sequencing a cDNA fragment derived from human brain mRNA after amplification by the polymerase chain reaction. The first intron is placed 7 bp upstream from the ATG translation start signal, whereas all other splice sites divide putative Ca2+-binding domains. All intron positions coincide exactly with those reported for the rat parvalbumin gene. The 5' mRNA leader sequence has a similarity of 57%, the coding region of 91% and the 3' non-coding region of 83% to the corresponding rat sequences. Only nine conservative amino acid replacements were observed between human and rat parvalbumins. The predicted secondary structures for human, rat, mouse and rabbit parvalbumins are very similar, indicating a strong structural relationship among mammalian parvalbumins. Several elements with potential transcription regulatory activities were found in the region immediately 5' to the transcription start site including a TATA box (TATATA) and a CAAT box (CCAAAAT). Several regions in the putative promoter are strongly conserved between the human and rat parvalbumin genes. One of these with a length of 32 bp is identical with the rat counterpart and has a high degree of homology to a promoter region in the myosin light chain 3F gene, which is expressed in fast contracting/relaxing muscle fibers (anaerobic/type IIb), the cell type that also exhibits highest levels of parvalbumin expression. The human parvalbumin mRNA contains the putative polyadenylation signal AATAAA 13 nucleotides upstream from the polyadenylation site. A 700-nucleotide long parvalbumin mRNA is synthesized at low levels in the human cerebellum as well as in the neuroblastoma cell line SK-N-BE.", "author" : [ { "dropping-particle" : "", "family" : "Berchtold", "given" : "M W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of molecular biology", "id" : "ITEM-2", "issue" : "3", "issued" : { "date-parts" : [ [ "1989", "12", "5" ] ] }, "page" : "417-27", "title" : "Parvalbumin genes from human and rat are identical in intron/exon organization and contain highly homologous regulatory elements and coding sequences.", "type" : "article-journal", "volume" : "210" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[22,23]", "plainTextFormattedCitation" : "[22,23]", "previouslyFormattedCitation" : "[22,23]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[22,23], and the methylation of this sequence has previously been shown to be increased following challenge by another neurotoxic factor, that of manganese ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "We have shown that maternal manganese (Mn) exposure caused sustained disruption of hippocampal neurogenesis of mouse offspring. To clarify the effects of maternal Mn exposure on epigenetic gene regulation contributing to the sustained disruption of hippocampal neurogenesis, we treated pregnant ICR mice with MnCl\u2082 in diet from gestational day 10 through day 21 after delivery on weaning and searched epigenetically downregulated genes by global promoter methylation analysis in the hippocampal dentate gyrus of male offspring on postnatal day (PND) 21 and PND 77. By CpG promoter microarray analysis on PND 21 following 800-ppm Mn exposure, sustained promoter hypermethylation and transcript downregulation through PND 77 were confirmed with Mid1, Atp1a3, and Nr2f1, whereas Pvalb showed a transient hypermethylation only on weaning. The numbers of Pvalb\u207a and ATP1a3\u207a neurons suggestive of \u03b3-aminobutyric acid (GABA)ergic interneurons, Mid1\u207a cells suggestive of late-stage granule cell lineage and GABAergic interneurons, and COUP-TF1\u207a cells suggestive of early-stage granule cell lineage were all reduced on PND 21, and reductions were sustained on PND 77 except for no change in Pvalb\u207a cells. Mid1\u207a cells showed asymmetric distribution with right-side predominance, and Mn exposure abolished it by promoter hypermethylation of the right side. These findings indicate epigenetic mechanisms as mediators, through which Mn exposure modulates neurogenesis involving both granule cell lineage and GABAergic interneurons with long-lasting and stable repercussions. Disruption of asymmetric cellular distribution of Mid1 suggests that higher brain functions specialized in the left or right side of the brain were affected.", "author" : [ { "dropping-particle" : "", "family" : "Wang", "given" : "Liyun", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shiraki", "given" : "Ayako", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Itahashi", "given" : "Megu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Akane", "given" : "Hirotoshi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Abe", "given" : "Hajime", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mitsumori", "given" : "Kunitoshi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shibutani", "given" : "Makoto", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Toxicological Sciences", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "154-165", "title" : "Aberration in epigenetic gene regulation in hippocampal neurogenesis by developmental exposure to manganese chloride in mice", "type" : "article-journal", "volume" : "136" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[13]", "plainTextFormattedCitation" : "[13]", "previouslyFormattedCitation" : "[13]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[13]. These authors showed effects of maternal manganese exposure on epigenetic gene regulation, with Pvalb promoter hypermethylation and transcript downregulation at the weaning stage in the offspring.The CpG sites studied here are at the 5’ boundary of a large CpG island with a high density of both CpG sites and transcription factor recognition sequences. These include multiple binding sites for Nrf2, several close to CpG2 and further CpG sites within the CpG island. Thus methylation in this sequence could conceivably modify Nrf2 binding and its associated transcriptional activity. Nrf2 has been identified as a transcription factor important in antioxidant effects on gene expression ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "Modulation of NF-E2 related factor 2 (Nrf2) has been shown in several neurodegenerative disorders. The overexpression of Nrf2 has become a potential therapeutic avenue for various neurodegenerative disorders such as Parkinson, Amyotrophic lateral sclerosis, and Alzheimer's disease. The expression of phase II detoxification enzymes is governed by the cis-acting regulatory element known as antioxidant response element (ARE). The transcription factor Nrf2 binds to ARE thereby transcribing multitude of antioxidant genes. Keap1, a culin 3-based E3 ligase that targets Nrf2 for degradation, sequesters Nrf2 in cytoplasm. Disruption of Keap1-Nrf2 interaction or genetic overexpression of Nrf2 can increase the endogenous antioxidant capacity of the brain thereby rendering protection against oxidative stress in neurodegenerative disorders. This review primarily focuses on recent patents that target Nrf2 overexpression as a promising therapeutic strategy for the treatment of neurodegenerative disorders.", "author" : [ { "dropping-particle" : "", "family" : "Joshi", "given" : "Gururaj", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "A. Johnson", "given" : "Jeffrey", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Recent Patents on CNS Drug Discovery", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2012" ] ] }, "page" : "218-229", "title" : "The Nrf2-ARE Pathway: A Valuable Therapeutic Target for the Treatment of Neurodegenerative Diseases", "type" : "article", "volume" : "7" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[24]", "plainTextFormattedCitation" : "[24]", "previouslyFormattedCitation" : "[24]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[24]. Given that the disruptive effects of repeated administration of another NMDA antagonist, ketamine, on PV neurons are mediated through oxidative damage ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1126/science.1148045", "ISSN" : "1095-9203", "PMID" : "18063801", "abstract" : "Abuse of the dissociative anesthetic ketamine can lead to a syndrome indistinguishable from schizophrenia. In animals, repetitive exposure to this N-methyl-d-aspartate-receptor antagonist induces the dysfunction of a subset of cortical fast-spiking inhibitory interneurons, with loss of expression of parvalbumin and the gamma-aminobutyric acid-producing enzyme GAD67. We show here that exposure of mice to ketamine induced a persistent increase in brain superoxide due to activation in neurons of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Decreasing superoxide production prevented the effects of ketamine on inhibitory interneurons in the prefrontal cortex. These results suggest that NADPH oxidase may represent a novel target for the treatment of ketamine-induced psychosis.", "author" : [ { "dropping-particle" : "", "family" : "Behrens", "given" : "M Margarita", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ali", "given" : "Sameh S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dao", "given" : "Diep N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lucero", "given" : "Jacinta", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shekhtman", "given" : "Grigoriy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Quick", "given" : "Kevin L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dugan", "given" : "Laura L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Science (New York, N.Y.)", "id" : "ITEM-1", "issue" : "5856", "issued" : { "date-parts" : [ [ "2007", "12", "7" ] ] }, "page" : "1645-7", "title" : "Ketamine-induced loss of phenotype of fast-spiking interneurons is mediated by NADPH-oxidase.", "type" : "article-journal", "volume" : "318" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[8]", "plainTextFormattedCitation" : "[8]", "previouslyFormattedCitation" : "[8]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[8] and that a natural antioxidant and potent activator of Nrf2 can protect against PCP-induced cognitive dysfunction ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1371/journal.pone.0127244", "abstract" : "Oxidative stress and inflammation play a role in cognitive impairment, which is a core symp-tom of schizophrenia. Furthermore, a hallmark of the pathophysiology of this disease is the dysfunction of cortical inhibitory \u03b3-aminobutyric acid (GABA) neurons expressing parvalbu-min (PV), which is also involved in cognitive impairment. Sulforaphane (SFN), an isothiocy-anate derived from broccoli, is a potent activator of the transcription factor Nrf2, which plays a central role in the inducible expressions of many cytoprotective genes in response to oxi-dative stress. Keap1 is a cytoplasmic protein that is essential for the regulation of Nrf2 activi-ty. Here, we found that pretreatment with SFN attenuated cognitive deficits, the increase in 8-oxo-dG-positive cells, and the decrease in PV-positive cells in the medial prefrontal cortex and hippocampus after repeated administration of phencyclidine (PCP). Furthermore, PCP-induced cognitive deficits were improved by the subsequent subchronic administration of SFN. Interestingly, the dietary intake of glucoraphanin (a glucosinolate precursor of SFN) during the juvenile and adolescence prevented the onset of PCP-induced cognitive deficits as well as the increase in 8-oxo-dG-positive cells and the decrease in PV-positive cells in the brain at adulthood. Moreover, the NRF2 gene and the KEAP1 gene had an epistatic ef-fect on cognitive impairment (e.g., working memory and processing speed) in patients with schizophrenia. These findings suggest that SFN may have prophylactic and therapeutic ef-fects on cognitive impairment in schizophrenia. Therefore, the dietary intake of SFN-rich broccoli sprouts during the juvenile and adolescence may prevent the onset of psychosis at adulthood.", "author" : [ { "dropping-particle" : "", "family" : "Shirai", "given" : "Yumi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fujita", "given" : "Yuko", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hashimoto", "given" : "Ryota", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ohi", "given" : "Kazutaka", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yamamori", "given" : "Hidenaga", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yasuda", "given" : "Yuka", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ishima", "given" : "Tamaki", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Suganuma", "given" : "Hiroyuki", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ushida", "given" : "Yusuke", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Takeda", "given" : "Masatoshi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hashimoto", "given" : "Kenji", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2015" ] ] }, "title" : "Dietary Intake of Sulforaphane-Rich Broccoli Sprout Extracts during Juvenile and Adolescence Can Prevent Phencyclidine- Induced Cognitive Deficits at Adulthood", "type" : "article-journal" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[25]", "plainTextFormattedCitation" : "[25]", "previouslyFormattedCitation" : "[25]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[25], these findings provide an intriguing mechanistic link between oxidative damage and PV deficits due to PCP administration.Reduced expression of PV is a well-established consequence of multiple dosing with NMDA antagonists such as PCP [1, 11]. Thus we suggest that this specific Pvalb hypermethylation may contribute to the decreased expression of PV mRNA and protein in the hippocampus and frontal cortex that is associated with sub-chronic PCP administration, although we have not reported corresponding expression data in this preliminary communication. However, measures of PV mRNA and protein expression do not always correspond ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/jnc.12061", "ISSN" : "1471-4159", "PMID" : "23083323", "abstract" : "Decreased parvalbumin expression is a hallmark of the pathophysiology of schizophrenia and has been associated with abnormal cognitive processing and decreased network specificity. It is not known whether this decrease is due to reduced expression of the parvalbumin protein or degeneration of parvalbumin-positive interneurons (PV(+) interneurons). In this study, we examined PV(+) expression in two rat models of cognitive dysfunction in schizophrenia: the environmental social isolation (SI) and pharmacological neonatal phencyclidine (neoPCP) models. Using a stereological method, the optical fractionator, we counted neurons, PV(+) interneurons, and glial cells in the medial prefrontal cortex (mPFC) and hippocampus (HPC). In addition, we quantified the mRNA level of parvalbumin in the mPFC. There was a statistically significant reduction in the number of PV(+) interneurons (p\u00a0=\u00a00.021) and glial cells (p\u00a0=\u00a00.024) in the mPFC of neonatal phencyclidine rats, but not in SI rats. We observed no alterations in the total number of neurons, hippocampal PV(+) interneurons, parvalbumin mRNA expression or volume of the mPFC or HPC in the two models. Thus, as the total number of neurons remains unchanged following phencyclidine (PCP) treatment, we suggest that the decreased number of counted PV(+) interneurons represents a reduced parvalbumin protein expression below immunohistochemical detection limit rather than a true cell loss. Furthermore, these results indicate that the effect of neonatal PCP treatment is not limited to neuronal populations.", "author" : [ { "dropping-particle" : "", "family" : "Kaalund", "given" : "Sanne S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Riise", "given" : "Jesper", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V", "family" : "Broberg", "given" : "Brian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fabricius", "given" : "Katrine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Karlsen", "given" : "Anna S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Secher", "given" : "Thomas", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Plath", "given" : "Niels", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pakkenberg", "given" : "Bente", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of neurochemistry", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2013", "2" ] ] }, "page" : "548-57", "title" : "Differential expression of parvalbumin in neonatal phencyclidine-treated rats and socially isolated rats.", "type" : "article-journal", "volume" : "124" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1016/j.neuint.2009.10.011", "ISSN" : "1872-9754", "PMID" : "19897002", "abstract" : "The psychotomimetic effect of NMDA antagonists such as phencyclidine (PCP) in humans spurred the hypoglutamatergic theory of schizophrenia. This theory is supported by animal studies demonstrating schizophrenia-like behavioral and molecular changes following PCP administration to adult or neonatal animals. However, schizophrenia is believed to develop in part due to neurodevelopmental dysfunction during adolescence. Therefore, the effects of PCP in juvenile animals may better reflect the pathophysiology of schizophrenia. Here, we compare the effect of PCP (5mg/kg/day for 5 days) on activity-regulated cytoskeleton-associated protein (Arc) and parvalbumin mRNA expression in juvenile and adult rats. Arc is a marker for excitatory neurotransmission. Parvalbumin is a marker for GABAergic neurotransmission, known to be reduced in postmortem brains of schizophrenics. PCP reduced parvalbumin mRNA expression in the medial prefrontal cortex (mPFC), ventrolateral orbitofrontal cortex (VLO) and shell of the nucleus accumbens (ACCshell) in both juvenile and adult rats. Contrarily, PCP produced opposite effects on Arc mRNA expression in the mPFC, VLO and ACCshell, leading to decreased expression in juvenile and increased expression in adult rats. The differential effect of PCP in juvenile and adult rats may be caused by the immature functional state of the prefrontal cortex in juvenile rats. These results demonstrate differences between the effects of PCP in juvenile and adult rats. The decrease in Arc mRNA in juvenile rats corresponds best with the proposed \"hypofrontality\" in schizophrenia, suggesting the merits of using PCP in juvenile animals as a model for schizophrenia, as this would relate better to the typical onset and clinical features of schizophrenia.", "author" : [ { "dropping-particle" : "", "family" : "Thomsen", "given" : "Morten S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hansen", "given" : "Henrik H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mikkelsen", "given" : "Jens D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neurochemistry international", "id" : "ITEM-2", "issue" : "2", "issued" : { "date-parts" : [ [ "2010", "1" ] ] }, "page" : "270-5", "title" : "Opposite effect of phencyclidine on activity-regulated cytoskeleton-associated protein (Arc) in juvenile and adult limbic rat brain regions.", "type" : "article-journal", "volume" : "56" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[26,27]", "plainTextFormattedCitation" : "[26,27]", "previouslyFormattedCitation" : "[26,27]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[26] and it is not possible to demonstrate a causal effect of PCP-induced changes in methylation on PV expression with this model. Thus we cannot rule out the possibility that DNA hypermethylation and reduced expression of PV are independent consequences of subchronic NMDA receptor antagonism by PCP. 5. Conclusion and Future PerspectivesThis preliminary study demonstrates that sub-chronic PCP administration to rats 6 weeks previously, and resulting in a cognitive deficit, can also have a specific and enduring effect on DNA methylation in the promoter region of Pvalb. Much more needs to be done to fully understand the process and effects of this Pvalb promoter hypermethylation. It would be important to determine whether Pvalb methylation parallels the time course of PV deficits and the protective effects of antioxidant or other pharmacological intervention. We have studied what is likely to be a functionally important sequence within the promoter region of Pvalb, but further sequences important in transcriptional activity need to be investigated. Although the finding is independent of one measure of global DNA methylation, it may well be that other specific genes may also demonstrate changes in DNA methylation, particularly those implicated in the GABAergic deficits following PCP administration such as those of GAD67 expression ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.neuropharm.2011.01.008", "ISBN" : "1873-7064 (Electronic)\\r0028-3908 (Linking)", "ISSN" : "00283908", "PMID" : "21238466", "abstract" : "Repeated phencyclidine (PCP) administration induces cognitive disruptions resembling those seen in schizophrenia. Alterations in glutamate transmission and ??-aminobutyric acid (GABA) function in the prefrontal cortex (PFC) have been implicated in these PCP-induced deficits, as well as in cognitive symptoms of schizophrenia. PCP-induced cognitive deficits are reversed by chronic treatment with the atypical antipsychotic clozapine in rats. We investigated the effects of a single injection vs. repeated administration of PCP on glutamate levels in the PFC using in vivo microdialysis. Furthermore, we examined how these PCP regimens affect GABA neuronal markers in the PFC. Finally, we investigated the effects of clozapine on disruptions in glutamate levels and GABA neuronal markers induced by repeated PCP administration. Acute PCP administration (2 mg/kg) increased extracellular PFC glutamate; this increase appeared blunted, but was not eliminated, after repeated PCP pretreatment. PCP administration also strongly decreased levels of parvalbumin and glutamic acid decarboxylase-67 (two markers of GABA function) in the PFC, an effect that was maintained after a 10 day drug-free washout period and unaltered by the resumption of repeated PCP injections. All of the observed PCP effects were attenuated by chronic treatment with clozapine, an atypical antipsychotic that has partial effectiveness on cognitive impairment in schizophrenia. These findings suggest that abnormal cortical glutamate transmission, possibly driven by pathological changes in GABA function in parvalbumin-positive fast-spiking interneurons, may underlie some of the cognitive deficits in schizophrenia. A better understanding of glutamate and GABA dysregulation in schizophrenia may uncover new treatment targets for schizophrenia-related cognitive dysfunction. This article is part of a Special Issue entitled 'Schizophrenia'. ?? 2011 Elsevier Ltd. All rights reserved.", "author" : [ { "dropping-particle" : "", "family" : "Amitai", "given" : "Nurith", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kuczenski", "given" : "Ronald", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Behrens", "given" : "M. Margarita", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Markou", "given" : "Athina", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neuropharmacology", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2012" ] ] }, "title" : "Repeated phencyclidine administration alters glutamate release and decreases GABA markers in the prefrontal cortex of rats", "type" : "article-journal" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[28]", "plainTextFormattedCitation" : "[28]", "previouslyFormattedCitation" : "[28]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[27] and calbindin ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "Background: Postmortem studies have provided evidence for abnormalities of the ??-aminobutyric acid (GABA)ergic system in schizophrenia, including deficits of GABA-containing interneurons. The calcium-binding proteins parvalbumin, calbindin, and calretinin can be used as markers for specific subpopulations of cortical GABAergic interneurons. Methods: Following our previous observation of a reduction in the density of parvalbumin- but not calretinin-immunoreactive cells in the prefrontal cortex (Brodmann area 10) in schizophrenia, we have quantified the laminar density of neurons immunoreactive for the calcium-binding proteins parvalbumin, calbindin, and calretinin in a further prefrontal cortical region (Brodmann area 9) in patients with schizophrenia, bipolar disorder, major depression, and in matched control subjects (each group n = 15). Results: Initial statistical analysis revealed reductions in the total cortical density of parvalbumin- and calbindin- but not calretinin-immunoreactive neurons in schizophrenia relative to control subjects. Further analysis comparing individual laminar densities between groups indicated that, following correction for multiple comparisons, only a reduction in calbindin-immunoreactive neurons in cortical layer II in the schizophrenic group attained statistical significance. Conclusions: These findings suggest that deficits of specific GABAergic neurons, defined by the presence of calcium-binding proteins, are present in schizophrenia. Trends toward similar reductions are observed in bipolar disorder. ?? 2002 Society of Biological Psychiatry.", "author" : [ { "dropping-particle" : "", "family" : "Beasley", "given" : "Clare L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhang", "given" : "Zhi J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Patten", "given" : "Iain", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Reynolds", "given" : "Gavin P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Biological Psychiatry", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2002" ] ] }, "page" : "708-715", "title" : "Selective deficits in prefrontal cortical GABAergic neurons in schizophrenia defined by the presence of calcium-binding proteins", "type" : "article-journal", "volume" : "52" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[29]", "plainTextFormattedCitation" : "[29]", "previouslyFormattedCitation" : "[29]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[28]. Most important would be to determine whether hypermethylation of the PV gene occurs in psychotic illness including schizophrenia, for which sub-chronic PCP administration can model both PV deficits and certain symptoms ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.pharmthera.2010.07.004", "ISSN" : "1879-016X", "PMID" : "20705091", "abstract" : "Cognitive deficits in schizophrenia remain an unmet clinical need. Improved understanding of the neuro- and psychopathology of these deficits depends on the availability of carefully validated animal models which will assist the development of novel therapies. There is much evidence that at least some of the pathology and symptomatology (particularly cognitive and negative symptoms) of schizophrenia results from a dysfunction of the glutamatergic system which may be modelled in animals through the use of NMDA receptor antagonists. The current review examines the validity of this model in rodents. We review the ability of acute and sub-chronic treatment with three non-competitive NMDA antagonists; phencyclidine (PCP), ketamine and MK801 (dizocilpine) to produce cognitive deficits of relevance to schizophrenia in rodents and their subsequent reversal by first- and second-generation antipsychotic drugs. Effects of NMDA receptor antagonists on the performance of rodents in behavioural tests assessing the various domains of cognition and negative symptoms are examined: novel object recognition for visual memory, reversal learning and attentional set shifting for problem solving and reasoning, 5-Choice Serial Reaction Time for attention and speed of processing; in addition to effects on social behaviour and neuropathology. The evidence strongly supports the use of NMDA receptor antagonists to model cognitive deficit and negative symptoms of schizophrenia as well as certain pathological disturbances seen in the illness. This will facilitate the evaluation of much-needed novel pharmacological agents for improved therapy of cognitive deficits and negative symptoms in schizophrenia.", "author" : [ { "dropping-particle" : "", "family" : "Neill", "given" : "Joanna C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Barnes", "given" : "Samuel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cook", "given" : "Samantha", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Grayson", "given" : "Ben", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Idris", "given" : "Nagi F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McLean", "given" : "Samantha L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Snigdha", "given" : "Shikha", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rajagopal", "given" : "Lakshmi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Harte", "given" : "Michael K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pharmacology & therapeutics", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2010", "12" ] ] }, "page" : "419-32", "title" : "Animal models of cognitive dysfunction and negative symptoms of schizophrenia: focus on NMDA receptor antagonism.", "type" : "article-journal", "volume" : "128" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "[30]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }[29].Executive SummaryBackground ?Subchronic phencyclidine (PCP) administration to rats can produce enduring deficits in the calcium binding protein parvalbumin (PV) in GABAergic neurons; these resemble equivalent deficits in schizophrenia.?Effects on DNA methylation may contribute to these PV deficits.Results?We found increased brain DNA methylation at one site in the PV gene promoter following subchronic PCP administration to rats.?This increase in methylation is specific to a site within a transcription factor binding sequence.?No differences were found in a global measure of DNA methylation.Conclusion?PCP sub-chronic administration to rats results in hypermethylation of a specific site in the promoter sequence of the PV gene.?This hypermethylation may, through effects on transcription, contribute to the enduring reduction in PV following PCP administration.6. Financial Disclosure and AcknowledgementsHA Fachim has received a scholarship from CNPq and research funding from FAPESP (process no 2015/02948-7) in part support of this work. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.7. Ethical Conduct of ResearchThe authors state that they have obtained appropriate institutional review board approval and have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations.8. References ADDIN Mendeley Bibliography CSL_BIBLIOGRAPHY 1. Cochran SM, Kennedy M, McKerchar CE, Steward LJ, Pratt JA, Morris BJ. Induction of metabolic hypofunction and neurochemical deficits after chronic intermittent exposure to phencyclidine: differential modulation by antipsychotic drugs. Neuropsychopharmacology. 28(2), 265–275 (2003).2. Abdul-Monim Z, Neill JC, Reynolds GP. Sub-chronic psychotomimetic phencyclidine induces deficits in reversal learning and alterations in parvalbumin-immunoreactive expression in the rat. J. Psychopharmacol. 21(2), 198–205 (2007).3. Beasley CL, Reynolds GP. Parvalbumin-immunoreactive neurons are reduced in the prefrontal cortex of schizophrenics. Schiz. Res. 24(3), 349–355 (1997).* This was the first of many reports indicating losses of PV in the brain in schizophrenia4. Zhang ZJ, Reynolds GP. A selective decrease in the relative density of parvalbumin-immunoreactive neurons in the hippocampus in schizophrenia. Schiz. Res. 55, 1-10 (2002).5. Harte MK, Powell SB, Swerdlow NR, Geyer MA, Reynolds GP. Deficits in parvalbumin and calbindin immunoreactive cells in the hippocampus of isolation reared rats. J. Neural Transm. 114(7), 893–8 (2007). 6. Jenkins TA, Harte MK, Stenson G, Reynolds GP. Neonatal lipopolysaccharide induces pathological changes in parvalbumin immunoreactivity in the hippocampus of the rat. Behav. Brain Res. 205(2), 355–359 (2009).7. Penschuck S, Flagstad P, Didriksen M, Leist M, Michael-Titus AT. Decrease in parvalbumin-expressing neurons in the hippocampus and increased phencyclidine-induced locomotor activity in the rat methylazoxymethanol (MAM) model of schizophrenia. Eur. J. Neurosci. 23(1), 279–84 (2006). 8. Behrens MM, Ali SS, Dao DN, et al. Ketamine-induced loss of phenotype of fast-spiking interneurons is mediated by NADPH-oxidase. Science. 318(5856), 1645–7 (2007). *An interesting finding demonstrating the role of reactive oxygen species in the toxic effects on NMDA antagonists on PV-containing neurons.9. Sabbagh JJ, Murtishaw AS, Bolton MM, Heaney CF, Langhardt M, Kinney JW. Chronic ketamine produces altered distribution of parvalbumin-positive cells in the hippocampus of adult rats. Neurosci. Lett. 550, 69–74 (2013).10. Morshedi MM, Meredith GE. Differential laminar effects of amphetamine on prefrontal parvalbumin interneurons. Neuroscience. 149(3), 617–624 (2007).11. Pratt JA, Winchester C, Egerton A, Cochran SM, Morris BJ. Modelling prefrontal cortex deficits in schizophrenia: implications for treatment. Br. J. Pharmacol. 153 Suppl , S465–S470 (2008).12. Grayson DR, Guidotti A. The dynamics of DNA methylation in schizophrenia and related psychiatric disorders. Neuropsychopharmacology 38(1), 138–66 (2013). 13. Wang L, Shiraki A, Itahashi M, et al. Aberration in epigenetic gene regulation in hippocampal neurogenesis by developmental exposure to manganese chloride in mice. Toxicol. Sci. 136(1), 154–165 (2013).*This paper first reports hypermethylation of the PV gene promoter following a neurotoxic challenge.14. Thomas CA, Paquola ACM, Muotri AR. LINE-1 Retrotransposition in the Nervous System. Annu. Rev. Cell Dev. Biol. 28(1), 555–573 (2012).15. Rosser JM. L1 expression and regulation in humans and rodents. Front. Biosci. E4(1), 2203 (2012).16. Grayson B, Idris NF, Neill JC. Atypical antipsychotics attenuate a sub-chronic PCP-induced cognitive deficit in the novel object recognition task in the rat. Behav. Brain Res. 184(1), 31–8 (2007). 17. Tryndyak VP, Kovalchuk O, Muskhelishvili L, et al. Epigenetic reprogramming of liver cells in tamoxifen-induced rat hepatocarcinogenesis. Mol. Carcinog. 46(3), 187–197 (2007).18. Cochran SM, Fujimura M, Morris BJ, Pratt JA. Acute and delayed effects of phencyclidine upon mRNA levels of markers of glutamatergic and GABAergic neurotransmitter function in the rat brain. Synapse. 46(3), 206–214 (2002).* The first observation of diminished PV mRNA following sub-chronic PCP administration.19. Ryan J, Saffery R. Crucial timing in schizophrenia: role of DNA methylation in early neurodevelopment. Genome Biol. 15(10), 495 (2014). 20. Kundakovic M, Gudsnuk K, Herbstman JB, Tang D, Perera FP, Champagne FA. DNA methylation of BDNF as a biomarker of early-life adversity. Proc. Natl. Acad. Sci. U. S. A. 112(22), 6807–13 (2015). 21. Jones PL, Veenstra GJ, Wade PA, et al. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat. Genet. 19(2), 187–91 (1998). 22. Berchtold MW, Epstein P, Beaudet AL, Payne ME, Heizmann CW, Means AR. Structural organization and chromosomal assignment of the parvalbumin gene. J. Biol. Chem. 262(18), 8696–8701 (1987).23. Berchtold MW. Parvalbumin genes from human and rat are identical in intron/exon organization and contain highly homologous regulatory elements and coding sequences. J. Mol. Biol. 210(3), 417–27 (1989). 24. Joshi G, A. Johnson J. The Nrf2-ARE Pathway: A Valuable Therapeutic Target for the Treatment of Neurodegenerative Diseases. Recent Pat. CNS Drug Discov. 7(3), 218–229 (2012).25. Shirai Y, Fujita Y, Hashimoto R, et al. Dietary Intake of Sulforaphane-Rich Broccoli Sprout Extracts during Juvenile and Adolescence Can Prevent Phencyclidine-Induced Cognitive Deficits at Adulthood. PLoS One 10(6), e0127244 (2015).26. Kaalund SS, Riise J, Broberg B V, et al. Differential expression of parvalbumin in neonatal phencyclidine-treated rats and socially isolated rats. J. Neurochem. 124(4), 548–57 (2013). 27. Amitai N, Kuczenski R, Behrens MM, Markou A. Repeated phencyclidine administration alters glutamate release and decreases GABA markers in the prefrontal cortex of rats. Neuropharmacology. (2012).28. Beasley CL, Zhang ZJ, Patten I, Reynolds GP. Selective deficits in prefrontal cortical GABAergic neurons in schizophrenia defined by the presence of calcium-binding proteins. Biol. Psychiatry. 52(7), 708–715 (2002).29. Neill JC, Barnes S, Cook S, et al. Animal models of cognitive dysfunction and negative symptoms of schizophrenia: focus on NMDA receptor antagonism. Pharmacol. Ther. 128(3), 419–32 (2010). Figure LegendFigure 1. Mean percentage of methylation in the Pvalb promoter sequence in hippocampal and prefrontal cortex tissue samples in rats undergoing PCP or vehicle. Bars represent SEM.*p <0.05.Figure 1.02286000 ................
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