Synaptic transmission



Synaptic transmission



General principles


The majority of synapses in the brain and spinal cord are chemical, meaning that the communication between nerve cells is mediated by a neurotransmitter substance. Electrical synapses are much less common and can be used to synchronize activity in a group of neurons.



Electrical synapses


Electrical synapses are also known as gap junctions and are direct points of contact between the cytoplasm of adjacent neurons (Greek: sunapsis, point of contact). This allows very rapid two-way communication and synchronization of electrical discharges.


A gap junction is composed of around 100 intercellular channels called connexons that are inserted into the plasma membranes of adjacent cells (Fig. 7.1). Each connexon is composed of a hexagonal array of proteins called connexins, surrounding an aqueous channel that is 2 nm wide. The pores in adjacent cell membranes are aligned to form a ‘tunnel’ between the two cells. These can be opened or closed by a conformational change in the constituent proteins, regulated by phosphorylation state.



Gap junctions represent a low-resistance pathway that allows charged particles and small molecules to flow freely in either direction and couples the electrical activity of adjoining cells. Groups of cells linked by gap junctions form an electrical syncytium which can generate large, synchronized discharges. This happens in certain brain stem nuclei that control breathing and may contribute to the generation of abnormally synchronized discharges in some forms of epilepsy (Ch. 11).



Chemical synapses


Most central nervous system synapses are chemical. The general structure and arrangement is similar to that of the neuromuscular junction (see Ch. 4) and a great deal of information about central synapses has been derived from experiments at the point of contact between nerve and muscle.



General structure (Fig. 7.2)


At a chemical synapse the plasma membranes of the two nerve cells are in close proximity, separated by a narrow synaptic cleft. The axon terminal of the presynaptic neuron contains membrane-bound synaptic vesicles that are loaded with neurotransmitter; it also contains numerous mitochondria to provide energy for neurotransmission.



Peptide transmitters are synthesized in the cell body and pre-loaded into vesicles which are delivered to the axon terminal by fast axonal transport (see Ch. 5). Other transmitters are synthesized within the axon terminal and are loaded into synaptic vesicles by transport pumps in the vesicle membrane. Some are synthesized within the vesicle itself.




Excitatory and inhibitory synapses (Fig. 7.3)


Synapses can be excitatory or inhibitory. If the presynaptic neuron releases an excitatory transmitter (most commonly glutamate) then the membrane of the postsynaptic cell will be depolarized. This is referred to as an excitatory post-synaptic potential (EPSP) and is typically associated with an inward sodium current. If the presynaptic neuron releases an inhibitory neurotransmitter (the most common of which is gamma-aminobutyric acid or GABA) then the postsynaptic membrane will be hyperpolarized (inhibited). This is an inhibitory postsynaptic potential (IPSP) and is often associated with an inward chloride current (or an outward potassium current). EPSPs and IPSPs are graded potentials of a few millivolts that only influence the local membrane and then rapidly decay (see Ch. 6).




Release of neurotransmitter (Fig. 7.4)


Once loaded with neurotransmitter, synaptic vesicles are docked at the presynaptic membrane awaiting release. Docking takes place at active zones. These consist of multi-protein complexes that tether the synaptic vesicle to the presynaptic membrane and contain high concentrations of voltage-gated calcium channels. This leads to brisk calcium influx in response to axon terminal depolarization, since the concentration of calcium is 10,000 times higher in the extracellular fluid. The focal rise in free calcium causes a number of synaptic vesicles to fuse with the presynaptic membrane, emptying their contents into the synaptic cleft by exocytosis.



Release is said to be ‘packeted’ (or quantized) since the total amount of transmitter entering the synaptic cleft is a whole-number multiple of the amount stored in a single vesicle. Transmitter release is regulated by presynaptic autoreceptors which exert negative feedback.




Transmitter inactivation


To ensure that neurotransmission is a discrete event, the transmitter substance must be quickly removed from the synaptic cleft. In the case of acetylcholine this is achieved by enzymatic degradation (by acetylcholinesterase) but in most cases the transmitter molecule is reclaimed by the presynaptic neuron via membrane-bound reuptake proteins and recycled into new synaptic vesicles. Postsynaptic cells (and surrounding glia) also take up and metabolize neurotransmitters.


The entire process of synaptic transmission, from the arrival of the nerve impulse at the presynaptic element to the generation of a new nerve impulse in the postsynaptic cell, incurs a synaptic delay which may be up to five milliseconds. Chemical synapses are thus much slower than electrical synapses. However, each synaptic station in a neural pathway provides an opportunity for impulse traffic to be modulated or filtered.




Neurotransmitters


Approximately 50 to 100 substances are known (or suspected) to be neurotransmitters in the central nervous system. The reason that many of these chemicals are referred to as suspected or putative transmitters is that it is surprisingly difficult to prove that a substance is acting as a neurotransmitter, particularly in the human brain. This is because nervous tissue is densely packed with neurons, glial cells and blood vessels, surrounded by extracellular fluid in which there are numerous transmitters, peptides and hormones – and because synaptic events are fleeting and occur on a microscopic scale.


A number of criteria must be satisfied to establish that a substance is a neurotransmitter. It must be demonstrated that the candidate molecule: (i) is synthesized in the presynaptic neuron; (ii) is present within the axon terminal; and (iii) is released in a calcium-dependent manner upon depolarization of the presynaptic cell. It must also be shown that exogenous application of the substance has the same effect on the target cell as depolarizing the presynaptic cell. Relatively few molecules have satisfied these strict criteria unequivocally.



Classical neurotransmitters


Classical, small molecule neurotransmitters are stored in clear-cored vesicles that are approximately 50 nm in diameter. The first to be identified was acetylcholine (ACh) and it remains the best understood. Acetylcholine is found at the neuromuscular junction and throughout the autonomic nervous system. It differs from other types of neurotransmitter and has a distinct chemical structure, biosynthesis and mechanism of inactivation (Fig. 7.5). Acetylcholine is synthesized in axon terminals from two metabolites that are present in all cells: acetyl-coA and choline. This is achieved by the enzyme choline acetyltransferase (ChAT) which is only present in cholinergic neurons. The remaining small molecule neurotransmitters are divided into amino acids and biogenic amines.


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Jun 19, 2016 | Posted by in NEUROLOGY | Comments Off on Synaptic transmission

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