Neurotransmission



Neurotransmission

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Chemical synapses are specialized junctions through which neurons signal to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous system.

The adult human brain is estimated to contain from 1014 to 5 × 1014 (100-500 trillion) synapses. Each mm3 of cerebral cortex contains roughly a billion of them.

Synapses are functional connections between neurons, or between neurons and other types of cells. A typical neuron gives rise to several thousand synapses, although there are some types that make far fewer. Most synapses connect axons to dendrites, but there are also other types of connections, including axon-to-cell-body, axon-to-axon, and dendrite-to-dendrite

Chemical synapses pass information directionally from a presynaptic cell to a postsynaptic cell and are therefore asymmetric in structure and function. The presynaptic terminal, or synaptic bouton, is a specialized area within the axon of the presynaptic cell that contains neurotransmitters enclosed in small membrane-bound spheres called synaptic vesicles.

Immediately opposite is a region of the postsynaptic cell containing neurotransmitter receptors; for synapses between two neurons the postsynaptic region may be found on the dendrites or cell body. Immediately behind the postsynaptic membrane is an elaborate complex of interlinked proteins called the Post Synaptic Density (PSD).

Proteins in the PSD are involved in anchoring and trafficking neurotransmitter receptors and modulating the activity of these receptors. The receptors and PSDs are often found in specialized protrusions from the main dendritic shaft called dendritic spines.

Between the pre- and postsynaptic cells is a gap about 20 nm wide called the Synaptic Cleft. The small volume of the cleft allows neurotransmitter concentration to be raised and lowered rapidly. The membranes of the two adjacent cells are held together by cell adhesion proteins.

The sequence of events that take place in synaptic transmission from a presynaptic neuron to a postsynaptic cell as follows.

The process begins with a wave of electrochemical excitation called an action potential traveling along the membrane of the presynaptic cell, until it reaches the synapse.

The electrical depolarization of the membrane at the synapse causes channels to open that are permeable to calcium ions.

Calcium ions flow through the presynaptic membrane, rapidly increasing the calcium concentration in the interior.

The high calcium concentration activates a set of calcium-sensitive proteins attached to vesicles that contain a neurotransmitter chemical.

These proteins change shape, causing the membranes of some "docked" vesicles to fuse with the membrane of the presynaptic cell, thereby opening the vesicles and dumping their neurotransmitter contents into the synaptic cleft, the narrow space between the membranes of the pre- and post-synaptic cells.

The neurotransmitter diffuses within the cleft. Some of it escapes, but some of it binds to chemical receptor molecules located on the membrane of the postsynaptic cell.

The binding of neurotransmitter causes the receptor molecule to be activated in some way. Several types of activation are possible, as described in more detail below. In any case, this is the key step by which the synaptic process affects the behavior of the postsynaptic cell.

Due to thermal shaking, neurotransmitter molecules eventually break loose from the receptors and drift away.

The neurotransmitter is either reabsorbed by the presynaptic cell, and then repackaged for future release, or else it is broken down metabolically.

The release of a neurotransmitter is triggered by the arrival of a nerve impulse (or action potential) and occurs through an unusually rapid process of cellular secretion, also known as exocytosis

The arriving action potential produces an influx of calcium ions through voltage-dependent, calcium-selective ion channels at the down stroke of the action potential (tail current). Calcium ions then trigger a biochemical cascade which results in vesicles fusing with the presynaptic membrane and releasing their contents to the synaptic cleft within 180µsec of calcium entry. Vesicle fusion is driven by the action of a set of proteins in the presynaptic terminal known as SNAREs.

As calcium ions enter into the presynaptic neuron, they bind with the proteins found within the membranes of the synaptic vesicles that allow the vesicles to "dock." Triggered by the binding of the calcium ions, the synaptic vesicle proteins begin to move apart, resulting in the creation of a fusion pore. The presence of the pore allows for the release of neurotransmitter into the synapse.

Receptor binding

Receptors on the opposite side of the synaptic gap bind neurotransmitter molecules and respond by opening nearby ion channels in the postsynaptic cell membrane, causing ions to rush in or out and changing the local transmembrane potential of the cell. The resulting change in voltage is called a postsynaptic potential.

Termination

After a neurotransmitter molecule binds to a receptor molecule, it does not stay bound forever: sooner or later it is shaken loose by random temperature-related jiggling. Once the neurotransmitter breaks loose, it can either drift away, or bind again to another receptor molecule. The pool of neurotransmitter molecules undergoing this binding-loosening cycle steadily diminishes, however. Neurotransmitter molecules are typically removed in one of two ways, depending on the type of synapse: either they are taken up by the presynaptic cell, or else they are broken down by special enzymes.

Synaptic transmission can be modulated by e.g. desensitization, homosynaptic plasticity and heterosynaptic plasticity:

Desensitization of the postsynaptic receptors is a decrease in response to the same neurotransmitter stimulus.

Homosynaptic plasticity is a change in the synaptic strength that results from the history of activity at a particular synapse.

Heterotropic plasticity is a change in synaptic strength that results for the activity of other neurons.

Effects of drugs

One of the most important features of chemical synapses is that they are the site of action for the majority of psychoactive drugs. Synapses are affected by drugs such as curare, strychnine, cocaine, morphine, alcohol, LSD, and countless others. These drugs have different effects on synaptic function, and often are restricted to synapses that use a specific neurotransmitter

The strength of a synapse is defined by the change in transmembrane potential resulting from activation of the postsynaptic neurotransmitter receptors. This change in voltage is known as a postsynaptic potential, and is a direct result of ionic currents flowing through the postsynaptic ion channels

An electrical synapse is a mechanical and electrically conductive link between two abutting neurons that is formed at a narrow gap between the pre- and postsynaptic cells known as a gap junction. At gap junctions, cells approach within about 3.5 nm of each other, rather than the 20 to 40 nm distance that separates cells at chemical synapses

A neuromuscular junction (NMJ) is the synapse or junction of the axon terminal of a motoneuron with the motor end plate, the highly-excitable region of muscle fiber plasma membrane responsible for initiation of action potentials across the muscle's surface, ultimately causing the muscle to contract. In vertebrates, the signal passes through the neuromuscular junction via the neurotransmitter acetylcholine.

Ribbon synapse is a type of synapse linking some neuronal cells and having unique features, such as high speed of neurotransmitter release and an ongoing cycle of exocytosis and endocytosis in response to graded changes of membrane potential. Ribbon synapses have been found in retinal photoreceptor cells, vestibular organ receptors, cochlear hair cells and retinal bipolar cells.

Neurotransmitters are endogenous chemicals which relay, amplify, and modulate signals between a neuron and another cell. Neurotransmitters are packaged into synaptic vesicles that cluster beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to receptors in the membrane on the postsynaptic side of the synapse

Major neurotransmitters:

Amino acids: glutamate, aspartate, serine, γ-aminobutyric acid (GABA), glycine

Monoamines: dopamine (DA), norepinephrine (noradrenaline; NE, NA), epinephrine (adrenaline), serotonin (SE, 5-HT), melatonin

Others: acetylcholine (ACh), adenosine, anandamide, histamine, nitric oxide, etc.

Glutamate is used at the great majority of fast excitatory synapses in the brain and spinal cord. It is also used at most synapses that are "modifiable", i.e. capable of increasing or decreasing in strength. Modifiable synapses are thought to be the main memory-storage elements in the brain.

GABA is used at the great majority of fast inhibitory synapses in virtually every part of the brain. Many sedative/tranquilizing drugs act by enhancing the effects of GABA. Correspondingly glycine is the inhibitory transmitter in the spinal cord.

Acetylcholine is distinguished as the transmitter at the neuromuscular junction connecting motor nerves to muscles. The paralytic arrow-poison curare acts by blocking transmission at these synapses. Acetylcholine also operates in many regions of the brain, but using different types of receptors.

Dopamine has a number of important functions in the brain. It plays a critical role in the reward system, but dysfunction of the dopamine system is also implicated in Parkinson's Disease and schizophrenia.

Serotonin has a number of important functions that are difficult to describe in a unified way, including regulation of mood, sleep/wake cycles, and body temperature. It is released during sunny weather, and also when eating chocolate.

Substance P undecapeptide responsible for transmission of pain from certain sensory neurons to the central nervous system.

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