Practically all animals can learn, but mammals seem to learn exceptionally well (or so we like to think). In a mammal’s brain, the region called the hippocampus has 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. Some synapses in the hippocampus show a striking form of synaptic plasticity with repeated use: whereas occasional single action potentials in the presynaptic cells leave no lasting trace, a short burst of repetitive firing causes long-term potentiation (LTP), such that subsequent single action potentials in the presynaptic cells evoke a greatly enhanced response in the postsynaptic cells. The effect lasts hours, days, or weeks, according to the number and intensity of the bursts of repetitive firing. Only the synapses that were activated exhibit LTP; synapses that have remained quiet on the same postsynaptic cell are not affected. However, while the cell is receiving a burst of repetitive stimulation via one set of synapses, if a single action potential is delivered at another synapse on its surface, that latter synapse also will undergo LTP, even though a single action potential delivered there at another time would leave no such lasting trace.
The underlying rule in such events seems to be that LTP occurs on any occasion when 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). 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 glutamate-gated ion channels are the most common of all transmitter-gated channels in the brain. In the hippocampus, as elsewhere, most of the depolarizing current responsible for excitatory PSPs is carried by glutamate-gated ion channels called AMPA receptors, which operate in the standard way (Figure 11–43). 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, so named 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 for releasing the Mg2+ that normally blocks the resting channel. This means that NMDA receptors are normally activated only when AMPA receptors are activated as well and depolarize the membrane. The NMDA receptors are critical for LTP. When they are selectively blocked with a specific inhibitor or inactivated genetically, LTP does not occur, even though ordinary synaptic transmission continues, indicating the importance of NMDA receptors
Figure 11–42 Structure of a Ca2+activated K+ channel. The channel contains four identical subunits (which are shown in different colors for clarity). It is both voltageand Ca2+-gated. The structure shown is a composite of the cytosolic and membrane portions of the channel that were separately crystallized. (PDB codes: 2R99, 1LNQ.)
Figure 11–43 The structure of the aMPa receptor. This ionotropic glutamate receptor (named after the glutamate analog α-Amino 3-hydroxy 5-Methyl 4-isoxazole Propionic Acid) is the most common mediator of fast, excitatory synaptic transmission in the central nervous system (CNS). (PDB code: 3KG2.)