synapse

synapse A specialized junction where transmission of information takes place between a nerve fibre and another nerve cell, or between a nerve fibre and a muscle or gland cell. The term was introduced at the end of the nineteenth century by the British neurophysiologist Charles Sherrington, who argued, on the basis of his own observations of reflex responses and the studies of the great Spanish anatomist, Ramón y Cajal, that a special form of transmission takes place at the contact between one cell and the next.

Synapses serve as one-way communication devices, transmitting information in one direction only, from the fibre ending to the next cell. They come in two varieties, known as chemical and electrical, according to the mechanism by which the signal is transmitted from the presynaptic to the postsynaptic cell. At electrical synapses, which are relatively rare in vertebrates, the membranes of the two cells are in tight contact, producing electrical coupling, which enables a nerve impulse (or action potential) arriving at the presynaptic nerve ending to pass swiftly and reliably to the next cell. Chemical synapses are more complex, because the presynaptic and postsynaptic cells are physically separated by a minute gap (the synaptic cleft), which prevents simple electrical transmission of the action potential to the postsynaptic cell. Instead, transmission is accomplished by the release of a chemical neurotransmitter substance from the presynaptic fibre.

The cytoplasm of the presynaptic nerve terminal (in a chemical synapse) is packed full of small vesicles, each containing a few thousand molecules of neurotransmitter. When an action potential arrives in the terminal it stimulates the opening of calcium channels in the terminal membrane. As a consequence, calcium ions flood into the cell and cause the synaptic vesicles to release their contents into the synaptic cleft. The neurotransmitter molecules that are liberated diffuse across the cleft and interact with specialized protein receptor molecules in the postsynaptic cell membrane. The molecular structure of the neurotransmitter and its receptor are matched, so that they fit one another like a lock and key. At nerve–muscle synapses, and in many nerve–nerve synapses, the receptors have a double function, since they also serve as ion channels. Binding of a neurotransmitter molecule produces a change in the three-dimensional shape of the receptor that opens a tiny intrinsic pore in the protein. In the case of neurotransmitters that excite the postsynaptic membrane, the pore permits positively-charged sodium ions to move into the cell, making the potential across its membrane less negative. This local depolarization is known as an excitatory synaptic potential, and its amplitude is determined by the number of vesicles released from the presynaptic cell. If it is sufficiently large, the synaptic potential initiates an action potential in the cell. If the target cell is a neuron, the action potential sweeps along its fibre. If it is a muscle, it also propagates over the surface of the muscle cell and causes it to contract.

Not all synaptic transmission is excitatory. Inhibitory transmitters also exist which render the post-synaptic cell less excitable and thus less likely to generate an action potential. They often act on receptors that act as channels for chloride ions, and generally make the interior of the postsynaptic cell even more negative (hyperpolarization). Acetylcholine is the excitatory transmitter at nerve–muscle synapses, and glutamate is the main excitatory transmitter in the central nervous system. Examples of inhibitory neurotransmitters include glycine and gamma aminobutyric acid (GABA).

The action of ‘fast’ neurotransmitters is brief, because they unbind quickly from their receptors and are then rapidly cleared from the synaptic cleft, usually by breakdown into inactive substances or reuptake into the cell. Because the receptor channels remain open only as long as neurotransmitter is bound, and because binding is only transient, the synaptic potential is also brief and the membrane potential returns rapidly to its resting level. Many other transmitters, sometimes called modulators (including serotonin, dopamine, noradrenaline, and many small peptide molecules), act more slowly and for much longer periods of time. In general, their receptors do not act as channels but instead activate messenger molecules inside the cell, which can initiate a variety of responses, even including the switching-on of genes in the chromosomes. It used to be thought that each nerve fibre releases only one neurotransmitter (‘Dale's principle’, after the British pharmacologist, Henry Dale), but it is now known that two or more transmitters and/or modulators can be produced by individual nerve terminals.

Each skeletal muscle fibre is innervated by a single excitatory nerve fibre, which discharges 100–300 vesicles for each arriving nerve impulse (enough to produce an action potential in the muscle cell). In contrast, a single nerve cell may have tens, or hundreds, of thousands of synapses. These are not only inhibitory as well as excitatory, but may involve many different type of transmitters and post-synaptic receptors (it is thought there may be more than 100 different neurotransmitters). Each pre-synaptic input may release just a few vesicles in response to a nerve impulse, so that the synaptic potential may be far smaller than that of a muscle fibre and many simultaneous or closely-successive inputs are needed to elicit one action potential. The output of the post-synaptic neuron will therefore be an integrated response to all of its many different inputs.

Most drugs that work on the brain, as well as drugs of abuse, act on synapses. One of the best known is nicotine, which activates acetylcholine receptors (its effect is mediated primarily at neuronal synapses in the brain). Curare, traditionally used by South American Indians as an arrow poison, paralysed the prey because it is an antagonist of the acetylcholine receptor and therefore blocks neuromuscular transmission. Morphine and heroin act on opiate receptors, and cannabis (unsurprisingly) on cannabinoid receptors. Cocaine works differently. It blocks the uptake system that clears the neurotransmitter dopamine from the synaptic cleft: consequently, dopamine hangs around for longer, which explains why cocaine acts as a stimulant. Some nerve gas poisons work in a similar fashion, by blocking the removal of the transmitter acetylcholine at nerve–muscle synapses.

A range of human diseases result from disorders of synaptic function. For instance, the inherited neuromuscular disorder, myasthenia gravis, occurs when the body produces antibodies to the acetylcholine receptors on muscle fibres. This causes them to be taken in by the cell, and the reduced number at the cell surface means that neurotransmission is compromised. Consequently, the patient is easily fatigued. Other myasthenias may result from a deficiency of the enzyme that breaks down acetylcholine, from presynaptic abnormalities that influence the amount of transmitter released, or from postsynaptic abnormalities associated with a reduction in the number or function of the acetylcholine receptors. Epilepsy is sometimes due to a decrease in the efficiency of inhibitory transmission in the brain, leading to over-excitability of networks of neurons. There is some evidence that the major psychiatric conditions, depression and schizophrenia, involve disorders of synapses in which serotonin and dopamine, respectively, act as neurotransmitters.

Frances M. Ashcroft

See also action potentials; motor neurons; nerves; nervous system; neuromuscular junction; neurotransmitters.