CHEMICAL SYNAPTIC TRANSMISSION
Chemical synaptic transmission proceeds in three steps: (1) The release of the transmitter substance from the bouton in response to the arrival of an action potential, (2) The change in the ionic permeabilities of the post-synaptic membrane caused by the transmitter, and (3) the removal of the transmitter from the synaptic cleft. Depending on the type of permeability changes produced in the second step, synaptic activation may have either an excitatory or an inhibitory effect on the post-synaptic cell.
Synaptic transmitter substances are concentrated in synaptic vesicles within the bouton. Although the exact mechanism of its release is unknown, it appears that the transmitter substance is released in packets, or quanta, of 1,000 to 10,000 molecules at a time, and that the probability of release of these quanta increases with the degree of depolarization of the terminal membrane. Thus the intense depolarization caused by an action potential actuates the nearly simultaneous release of a large number of quanta. A reasonable hypothesis to account for the quantal nature of transmitter release is that the contents of an entire vesicle are discharged at once into the synaptic cleft, perhaps by the process of exocytosis.
After their release, transmitter molecules diffuse across the synaptic cleft and combine with specific receptor molecules in the postsynaptic membrane. This combination gives rise to a change in the ionic permeability of the postsynaptic membrane and results in a flow of ions down their electrochemical potential gradients. This ionic flow is not synchronous with the arrival of the action potential in the terminal but begins after a synaptic delay of 0.3 to 0.5 msec, which is the time required for transmitter release and diffusion and for the completion of reactions within the postsynaptic membrane, which alter membrane permeability.
The direction of current flow produced by transmitter action depends upon which ionic permeabilities are altered. In an excitatory synapse, the transmitter causes an increase in the permeability of the postsynaptic membrane to sodium ions (Na+) and potassium ions (K+). Because of their respective concentration gradients across the neuronal membrane (see Plate 2-15), Na+ tends to move into the postsynaptic cell, and K+, out of it. The negative potential of the neuronal cytoplasm, however, assists the inward flow of positive ions and retards their outward flow so that the combined electrochemical force for Na+ influx greatly exceeds that for K+ efflux. Thus the predominant ionic movement across the postsynaptic membrane is an inward flow of Na+. As shown, the resulting current flow causes a shift of the postsynaptic cell membrane potential in the depolarizing direction. This depolarizing potential change, which is called an excitatory postsynaptic potential (EPSP), brings the postsynaptic cell closer to its threshold for action potential initiation.
In an inhibitory synapse, transmitter action causes an increase of the postsynaptic membrane’s permeability to K+ and chloride ions (Cl−) but not to Na+. Because Cl− is approximately at electrochemical equilibrium across the neuronal membrane, the major ionic movement is an outward flow of K+. The resulting current flow is in the opposite direction to that of the current flow in an excitatory synapse, and gives rise to a shift of the postsynaptic cell membrane potential in the hyperpolarizing direction. This hyperpolarizing potential change, which is called an inhibitory postsynaptic potential (IPSP), moves the membrane potential away from the threshold for action potential initiation. The increased ionic permeability of the postsynaptic membrane also contributes to the inhibitory effect by tending to “short out” any membrane depolarization occurring simultaneously.
The ionic current and the resulting membrane potential change have different time courses because the synaptic current charges the membrane capacitance, which then discharges passively over a period of 10 to 15 msec. The short duration of the synaptic current is the consequence of the removal of transmitter from the synaptic cleft. This removal is accomplished in part by passive diffusion and in part by specific mechanisms that lead to transmitter uptake by surrounding cells or transmitter breakdown by enzymatic degradation.