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SOME OF THE BRAIN’S MOST remarkable abilities, such as learning and memory, are thought to emerge from the elementary properties of chemical synapses, where the presynaptic cell releases chemical transmitters that activate receptors in the membrane of the postsynaptic cell. At most central synapses, transmitter is released from the presynaptic cell at presynaptic boutons, varicosities along the axon (like beads on a string) filled with synaptic vesicles and other organelles that contact postsynaptic targets. At other synapses, including the neuromuscular junction, transmitter is released from presynaptic terminals at the end of the axon. For convenience, we will refer to both types of release sites as presynaptic terminals. In the last three chapters, we saw how postsynaptic receptors control ion channels that generate the postsynaptic potential. Here we consider how electrical and biochemical events in the presynaptic terminal lead to the rapid release of small-molecule neurotransmitters, such as acetylcholine (ACh), glutamate, and γ-aminobutyric acid (GABA), that underlie fast synaptic transmission. In the next chapter, we examine the chemistry of the neurotransmitters themselves as well as the biogenic amines (serotonin, norepinephrine, and dopamine) and neuropeptides, which underlie slower forms of intercellular signaling.

Transmitter Release Is Regulated by Depolarization of the Presynaptic Terminal

What event at the presynaptic terminal leads to the release of transmitter? Bernard Katz and Ricardo Miledi first demonstrated the importance of depolarization of the presynaptic membrane. For this purpose, they used the giant synapse of the squid, a synapse large enough to permit insertion of electrodes into both pre- and postsynaptic structures. Two electrodes are inserted into the presynaptic terminal—one for stimulating and one for recording—and one electrode is inserted into the postsynaptic cell for recording the excitatory postsynaptic potential (EPSP), which provides an index of transmitter release (Figure 15–1A).

Figure 15–1

Transmitter release is triggered by changes in presynaptic membrane potential. (Adapted, with permission, from Katz and Miledi 1967a.)

A. Voltage recording electrodes are inserted in both the pre- and postsynaptic fibers of the giant synapse in the stellate ganglion of a squid. A current-passing electrode is also inserted presynaptically to elicit a presynaptic action potential.

B. Tetrodotoxin (TTX) is added to the solution bathing the cell to block the voltage-gated Na+ channels that underlie the action potential. The amplitudes of both the presynaptic action potential and the excitatory postsynaptic potential (EPSP) gradually decrease as more and more Na+ channels are blocked. After 7 minutes, the presynaptic action potential can still produce a suprathreshold EPSP that triggers an action potential in the postsynaptic cell. After about 14 to 15 minutes, the presynaptic spike gradually becomes smaller and produces smaller postsynaptic depolarizations. When the presynaptic spike is reduced to 40 mV or less, it fails to produce an EPSP. Thus, the size of the presynaptic depolarization (here provided by the action potential) controls the magnitude of transmitter release.

C. The dependence ...

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