Because they have been implicated in the basic processes of memory formation, NMDA receptors are currently being subjected to intense scrutiny by researchers. The NMDA receptor is one of the two main kinds of receptors activated by glutamate, which is a major excitatory synaptic transmitter found in all parts of the nervous system. The name NMDA receptor reflects the fact that this receptor is especially sensitive to the glutamate agonist N-methyl-D-aspartate. The other main kind of glutamate receptor is called the AMPA receptor because it is particularly sensitive to alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid. AMPA receptors and NMDA receptors often work in conjunction to produce long-lasting changes in synaptic functioning; this action is hypothesized to encode basic units of new memories.
The NMDA receptor acts differently from most receptor molecules because it is both ligand-gated and voltage-sensitive. When the NMDA receptor is activated, Ca2+ ions flow through its central channel into the neuron. But only very small amounts of Ca2+ flow through the NMDA receptor at the resting potential of –75 millivolts, or at any membrane potential between –75 and –35 millivolts. The reason for the low Ca2+ conductance at these membrane potentials is that magnesium ions (Mg2+) block the NMDA receptor’s central Ca2+ channel, as the left-hand panel of Figure 1 illustrates.
AMPA receptor activation allows Na+ ions to flow into the neuron, so sufficient activation of AMPA receptors can partially depolarize the membrane to less than –35 millivolts. This depolarization removes the Mg2+ block (see middle panel of Figure 1); the NMDA receptor now responds strongly and admits large amounts of Ca2+ through the channel. The Ca2+ starts a cascade of effects (described in more detail in Chapter 13) that results in more AMPA receptors (see right-hand panel of Figure 1). Thus, the NMDA receptor is fully active only when it is gated by a combination of voltage and ligand. Patch clamp studies show that the activation of NMDA receptors usually has a relatively slow onset and a prolonged effect (lasting up to 500 milliseconds), whereas non-NMDA receptors at the same synapse act rapidly, and their channels remain open only a few milliseconds at a time.
We can study the contributions of NMDA receptors by observing which functions are impaired or abolished by an NMDA antagonist. One such agent is aminophosphonovalerate (APV), which antagonizes the binding of glutamate to the NMDA receptor. Experiments with APV demonstrate that NMDA receptors are not needed for the normal flow of synaptic messages. But when the activity of other receptors reaches a relatively high level and partially depolarizes the membrane, NMDA receptors amplify and prolong the synaptic activity. These special properties allow the NMDA receptors to play a wide variety of important roles, especially in memory formation.
The search for new drugs that affect the NMDA receptor complex is intense (Kemp and McKernan, 2002). Given that NMDA receptors are involved in so many functions, new drugs may provide benefits ranging from improvements in cognitive function—because NMDA receptors are involved in memory processes—to minimizing the extent of neural damage following a stroke by countering glutamate’s neurotoxic effects.
Kemp, J. A., and McKernan, R. M. (2002). NMDA receptor pathways as drug targets. Nature Neuroscience 5(Suppl.): 1039–1042.