Practically all animals can learn, but mammals seem to learn exceptionally well (or so we like to

26 Practically all animals can learn, but mammals seem to learn exceptionally well (or so we like to

think). In a mammal's brain the hippocampus, a part of the cerebral cortex, plays a special role in learning: when it is destroyed on both sides of the brain, the ability to form new memories is largely lost, although previous long-established memories remain. Correspondingly, some think). In a mammal's brain the hippocampus, a part of the cerebral cortex, plays a special role in learning: when it is destroyed on both sides of the brain, the ability to form new memories is largely lost, although previous long-established memories remain. Correspondingly, some

a single action potential delivered there at another time would leave no such lasting trace. The underlying rule in the hippocampus seems to be that long-term potentiation occurs on any

occasion where a presynaptic cell fires (once or more) at a time when the postsynaptic membrane is strongly depolarized (either through recent repetitive firing of the same presynaptic cell or by other means). There is good evidence that this rule reflects the behavior of a particular class of ion channels in the postsynaptic membrane. Glutamate is the main excitatory neurotransmitter in the mammalian central nervous system, and in the hippocampus, as elsewhere, most of the depolarizing current responsible for excitatory PSPs is carried by glutamate-gated ion channels that operate in the standard way. But the current has in addition a second and more intriguing component, which is mediated by a separate subclass of glutamate- gated ion channels, known as NMDA receptors because they are selectively activated by the artificial glutamate analog N-methyl-D-aspartate. The NMDA-receptor channels are doubly gated, opening only when two conditions are satisfied simultaneously: glutamate must be bound to the receptor, and the membrane must be strongly depolarized. The second condition is required to release Mg 2+ that normally blocks the resting channel, and it means that NMDA receptors are normally only activated when conventional glutamate-gated ion channels are activated as well and depolarize the membrane. The NMDA receptors are critical for long-term potentiation. When they are selectively blocked with a specific inhibitor, long-term potentiation does not occur, even though ordinary synaptic transmission continues. An animal treated with this inhibitor shows specific deficits in its learning abilities but behaves almost normally otherwise.

How do the NMDA receptors mediate such a remarkable effect? The answer is that these channels, when open, are highly permeable to Ca 2+ , which acts as an intracellular mediator in the postsynaptic cell, triggering a cascade of changes that are responsible for long-term potentiation. Thus long-term potentiation is prevented when Ca 2+ levels are held artificially low in the postsynaptic cell by injecting the Ca 2+ chelator EGTA into it and can be induced by transiently raising extracellular Ca 2+ levels artificially high.

The long-term changes, although initiated in the postsynaptic cell, affect the presynaptic cell as well so that it releases more glutamate than normal when it is activated subsequently. The nature of the lasting change in the presynaptic cell is uncertain, but it is clear that some message must pass retrogradely from the postsynaptic cell to the presynaptic cell when long-term potentiation is induced. The nature of the retrograde signal is also unknown, although both nitric oxide and carbon monoxide have been suggested as candidates. A tentative model of some of the steps in the induction of long-term potentiation is presented in Figure 11-38. In addition to the long-lasting changes in the presynaptic cell illustrated in Figure 11-38, there are also long-lasting changes in the postsynaptic cell that contribute to long-term potentiation.

There is evidence that NMDA receptors play an important part in learning and related phenomena in other parts of the brain as well as in the hippocampus. In Chapter 21 we shall see, moreover, that NMDA receptors have a crucial role in adjusting the anatomical pattern of synaptic connections in the light of experience during the development of the nervous system.

Thus neurotransmitters released at synapses, besides relaying transient electrical signals, can also alter concentrations of intracellular mediators that bring about lasting changes in the efficacy of synaptic transmission. It is still uncertain, however, how these changes endure for weeks, months, or a lifetime in the face of the normal turnover of cell constituents.

Some of the ion channel families that we have discussed are summarized in Table 11-3.