Presynaptic Inhibition and Facilitation

Inhibition in the nervous system is sometimes accomplished indirectly by targeting excitatory presynaptic terminals, instead of the postsynaptic cell. This type of inhibition, called presynaptic inhibition, is illustrated schematically in Figure 9-14. The inhibitory terminal makes synaptic contact with an excitatory synaptic terminal, which in turn contacts the cell to be inhibited. Inhibition is produced by decreasing the release of excitatory neurotransmitter by the excitatory synaptic terminal. The electronmicrograph in Figure 9-14b shows a synaptic arrangement that might give rise to presynaptic inhibition.

Presynaptic inhibition often involves reduced calcium influx into the excitatory terminal during a presynaptic action potential. Reduced calcium influx during presynaptic inhibition results in some cases from decreased size or duration of the depolarization during the presynaptic action potential, which could be accomplished by activating potassium channels in the terminal. Smaller depolarization opens fewer voltage-sensitive calcium channels, and less calcium enters the excitatory terminal. In other cases, presynaptic inhibition involves reduced opening of voltage-sensitive calcium channels, possibly by decreased phosphorylation of the channels.

A synapse onto a synapse, such as the arrangement shown in Figure 9-14, might also facilitate rather than inhibit the release of neurotransmitter from the excitatory terminal. Presynaptic facilitation is known to occur, for example in the nervous system of a sea slug, Aplysia. The neurotransmitter serotonin increases the effectiveness of an excitatory synaptic connection from pre-synaptic sensory neurons onto postsynaptic motor neurons in Aplysia. The mechanism of the facilitation of synaptic transmission by serotonin is illustrated in Figure 9-15. Serotonin activates receptors that stimulate G-proteins in the synaptic terminal. One target of the G-proteins is adenylyl cyclase, which increases the concentration of cyclic AMP inside the synaptic terminal. This rise in cyclic AMP enhances neurotransmitter release in two ways. First, cyclic

Figure 9-14 (a) Schematic arrangement for presynaptic inhibition in the nervous system. The inhibitory terminal makes synaptic contact with another synaptic terminal, rather than directly with the postsynaptic cell. (b) Electronmicrograph showing a synapse (terminal 1) in the vertebrate central nervous system onto an axon (terminal 2) that in turn makes a synapse onto a third neuronal process (labeled "d" for dendrite). The arrows show the direction of synaptic transmission from terminal 1 to terminal 2 and from terminal 2 to the dendrite. Note the accumulations of synaptic vesicles in terminals 1 and 2. (Part (b) reproduced with permission from W. O. Wickelgren, Physiological and anatomical characteristics of reticulospinal neurones in lamprey. J. Physiol. 1977; 270:89-114.)

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Terminal 2
Presynaptic Serotonergic Receptors

Figure 9-15 A model for presynaptic changes associated with sensitization of the gill withdrawal reflex in Aplysia. The synaptic terminals of the facilitatory interneuron release the neurotransmitter serotonin, which combines with serotonin receptors in the membrane of the excitatory synaptic terminals of the gill withdrawal circuit. The activated receptor stimulates two G-proteins: one increases intracellular cyclic AMP via adenylyl cyclase, and a second activates protein kinase C. Cyclic AMP stimulates protein kinase A, which in turn phosphorylates and closes potassium channels. Reduced potassium permeability broadens the presynaptic action potential and enhances calcium influx through voltage-dependent calcium channels. In addition, protein kinase A and possibly protein kinase C may promote movement of synaptic vesicles from reserve pools to releasable pools, thereby potentiating transmitter release.

Figure 9-15 A model for presynaptic changes associated with sensitization of the gill withdrawal reflex in Aplysia. The synaptic terminals of the facilitatory interneuron release the neurotransmitter serotonin, which combines with serotonin receptors in the membrane of the excitatory synaptic terminals of the gill withdrawal circuit. The activated receptor stimulates two G-proteins: one increases intracellular cyclic AMP via adenylyl cyclase, and a second activates protein kinase C. Cyclic AMP stimulates protein kinase A, which in turn phosphorylates and closes potassium channels. Reduced potassium permeability broadens the presynaptic action potential and enhances calcium influx through voltage-dependent calcium channels. In addition, protein kinase A and possibly protein kinase C may promote movement of synaptic vesicles from reserve pools to releasable pools, thereby potentiating transmitter release.

AMP activates protein kinase A, which phosphorylates potassium channels (pathway A in Figure 9-15). The phosphorylated channels do not open during depolarization, which slows action potential repolarization and allows voltage-activated calcium channels to remain open for a longer time. Thus, a single action potential releases a greater amount of neurotransmitter. Second, the number of synaptic vesicles available to be released by a presynaptic action potential increases in response to cAMP. This effect may be generated by the movement of vesicles from a reserve group to the active zones, where they can fuse with the plasma membrane in response to calcium influx (pathway B in Figure 9-15). The molecular mechanism of this second action of cAMP remains unknown.

Evidence suggests that protein kinase C (PKC) may also be involved in enhancement of neurotransmitter release during sensitization. During sensit-ization, serotonin receptors indirectly activate PKC via a pathway initiated by a different subclass of G-proteins (Figure 9-15). Activation of PKC closes potassium channels and broadens action potentials, which potentiates calcium influx as described above. In addition, PKC may increase the pool of releasable synaptic vesicles at active zones.

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