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The physiological mechanisms by which one nerve cell (neuron) influences the activity of an anatomically adjacent neuron with which it is functionally coupled. Brain function depends on interactions of nerve cells with each other and with the gland cells and muscle cells they innervate. The interactions take place at specific sites of contact between cells known as synapses. The synapse is the smallest and most fundamental information-processing unit in the nervous system. By means of different patterns of synaptic connections between neurons, synaptic circuits are constructed during development to carry out the different functional operations of the nervous system.
The simplest type of synapse is the electrical synapse (see illustration), which consists of an area of unusually close contact between two cells packed with channels that span the two membranes and the cleft between them. Electrical synapses are also known as gap junctions. Electrical and metabolic communication between two cells is established by the components of the gap junctions. A variety of influences, including calcium ions, pH, membrane potential, neurotransmitters, and phosphorylating enzymes, may act on the channels to regulate their conductance in one direction (rectification) or both directions.
Electrical synapses are present throughout the animal kingdom. In vertebrates, they are numerous in the central nervous systems of fish as well as in certain nuclei of the mammalian brain, in regions where rapid transmission and synchronization of activity is important. Electrical synapses also interconnect glial cells in the brain. See Biopotentials and ionic currents, Cell permeability
The most prevalent type of junction between nerve cells is the chemical synapse (see illustration). At chemical synapses neurotransmitters are released from the presynaptic cell, diffuse across the synaptic clefts, and bind to receptors on the postsynaptic cell. Chemical synapses are found only between nerve cells or between nerve cells and the gland cells and muscle cells that they innervate. The neuromuscular junction, that is, the junction between the axon terminals of a motoneuron and a muscle fiber, is a prototypical chemical synapse. Three basic elements constitute this synapse: a presynaptic process (in this case, the motoneuron axon terminal) containing synaptic vesicles; an end plate (a specialized site of contact between the cells); and a postsynaptic process (in this case, the muscle cell). The postsynaptic membrane contains receptors for the transmitter substance released from the presynaptic terminal.
The chemical substance that serves as the transmitter at the vertebrate neuromuscular junction is acetylcholine (ACh). Within the nerve terminal, acetylcholine is concentrated within small spherical vesicles. At rest, these vesicles undergo exocytosis at low rates, releasing their acetylcholine in quantal packets to diffuse across the cleft and bind to and activate the postsynaptic receptors. Each quantum gives rise to a small depolarization of the postsynaptic membrane. These miniature end-plate potentials are rapid, lasting only some 10 milliseconds, and small in amplitude, only some 500 microvolts, below the threshold for effecting any response in the muscle. They represent the resting secretory activity of the nerve terminal.
When an organism wants to move its muscles, electrical impulses known as action potentials are generated in the motoneurons. These are conducted along the axon and invade the terminal, causing a large depolarization of the presynaptic membrane. This opens special voltage-gated channels for calcium ions, which enter the terminal and bind to special proteins, causing exocytosis of vesicles simultaneously. Calcium ions are the crucial link between the electrical signals in the presynaptic neuron and the chemical signals sent to the postsynaptic neuron. The combined action of this acetylcholine on postsynaptic receptors sets up a large postsynaptic depolarization, which exceeds the threshold for generating an impulse in the surrounding membrane, and causes the muscle to contract. The action of acetylcholine at its receptor is terminated by an enzyme, acetylcholinesterase, which is present in the synaptic cleft and hydrolyzes the acetylcholine to acetate and choline.
In order for neurotransmission to continue, synaptic vesicles have to be regenerated. Vesicles are rapidly and efficiently reformed in the nerve terminal by endocytosis. Specific neurotransmitter transporters within the membrane then fill the synaptic vesicle with appropriate neurotransmitter. The regenerated vesicle either returns to the plasma membrane where it rejoins the releasable pool of vesicles, or remains in the nerve terminal as part of a reserve pool. See Acetylcholine, Muscle
In the central nervous system the presynaptic process containing synaptic vesicles is most often an axon terminal and the postsynaptic process a dendrite, making an axodendritic synapse, but other relationships are also seen. The effect of transmitter on a postsynaptic cell is either excitatory or inhibitory, meaning that it either depolarizes or hyperpolarizes the membrane. Whether a transmitter has an excitatory or inhibitory effect on a cell is determined by the type of ion able to pass through the cell's receptor channels.
There are two principal types of central synapses.
Type 1 central synapses commonly release an amino acid transmitter, such as glutamate, whose action produces an excitatory postsynaptic potential. At low levels of activity the glutamate binds to the glutamate receptor and activates a relatively small conductance increase for sodium and potassium ions. Glutamate is the transmitter at many excitatory synapses throughout the central nervous system. The type 2 central synapse is usually associated with inhibitory synaptic actions. The most common inhibitory transmitter is gamma-amino butyric acid (GABA). Most inhibitory interneurons in different regions of the brain make these kinds of synapses on relay neurons in those regions. The GABA receptor is a complex channel-forming protein with several types of binding sites and several conductance states.
Other classes of synaptic transmitter substances include the biogenic amines, such as the catecholamines, norepinephrine and dopamine, and the indoleamine 5-hydroxytryptamine (also known as serotonin). See Dopamine, Noradrenergic system, Serotonin
A final type of transmitter substance consists of a vast array of neuropeptides. They are a diverse group and include substances that stimulate the release of hormones; those that act at synapses in pain pathways in the brain (the endogenous morphinelike substances, enkephalins and endorphins); and many of still undetermined functions. Peptides may act also indirectly, modifying the state of a receptor in its response to other transmitter substances, and they may do this in an activity-dependent manner. In view of the complexity and slow time course of many of their effects, these peptides are often referred to as neuromodulators. See Endorphins, Hormone
At central synapses, rapid responses to transmitters (typically within milliseconds) are most commonly the result of direct synaptic transmission, in which the receptor itself is the ion channel. Such receptors are referred to as ionotropic. There are, however, other receptor molecules for each of the neurotransmitters, and many of these are not themselves ion channels. They are known as metabotropic receptors, and they affect neurotransmission indirectly via a set of intermediary proteins called G-proteins. Activated G-proteins have a variety of effects on synaptic processes. Some are mediated by direct interactions with ion channels. However, many other effects are mediated by activation of cellular second messenger systems involving messengers such as calcium and cyclic adenosine monophosphate (cyclic AMP). The time courses for effects caused by activation of G-protein-coupled receptors is much longer than that of ionotropic channels (milliseconds), reflecting the lifetime of the activated G-protein subunits (seconds) and second messengers (seconds to minutes). Such longer lasting signals greatly increase the complexity of chemical neurotransmission and synaptic modulation. See Second messengers
The synapse is a dynamic structure whose function is very dependent on its activity state. In this way the synapse is constantly adjusted for its information load. At glutamatergic synapses, high levels of input activity bring about a different transmission state. The buildup of postsynaptic depolarization relieves the normal block of a specialized glutamate receptor channel, permitting influx of calcium ions into the postsynaptic process. Since the conductance of the channel is dependent on the depolarization state of the membrane, it is said to have a voltage-gated property, in addition to being ligand-gated by its transmitter. The calcium ion acts as a second messenger to bring about a long-lasting increase in synaptic efficacy, a process known as long-term potentiation. The conjunction of increased pre- and postsynaptic activity to give an increase in synaptic efficacy is called Hebbian, and is believed to be the type of plasticity mechanism involved in learning and memory. See Learning mechanisms, Memory
The synapse is one of the primary targets of drug actions. The first example to be identified was the arrow poison curare, which blocks neuromuscular transmission by binding to acetylcholine receptor sites. Many toxic agents have their actions on specific types of receptors; organic fluorophosphates, for example, are widely used pesticides that bind to and inactivate acetylcholinesterase. Most psychoactive drugs exert their effects at the synaptic level. See Nervous system (vertebrate), Neurobiology