NMDA Receptors and Disease+C464

N-Methyl-D-aspartate (NMDA) receptors are a major subtype of ionotropic excitatory glutamate receptors that mediate synaptic transmission at the vast majority of excitatory synapses in the central nervous system. Functional NMDA receptors are heterotetromeric complexes of NR1, NR2A–NR2D, and NR3A and NR3B subunits. The subunit compositions of the receptors affect both their functional properties and subcellular distributions. Like other types of ionotropic glutamate receptors, NMDA receptors are ion channels that allow major monovalent cations such as sodium and potassium to cross the plasma membrane, either into or out of the neuron, depending on the chemical and electrical gradients of these ions at a given time. However, NMDA receptors possess several unique properties that distinguish them from other ionotropic glutamate receptors. In addition to monovalent cations, NMDA receptors are also highly permeable to the divalent cation Ca2þ, which has numerous important intracellular functions. (Note: the only other type of glutamate receptor that exhibits similar Ca2þ permeability is the GluR2 subunit-lacking a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor, which represents a minor proportion of AMPA receptors in the brain.) The permeability of NMDA receptors to Ca2þ places them in a unique position to control the initiation of a lengthy list of Ca2þ-dependent cellular events.NMDA receptors also have two unique requirements that control their activation. Unlike other glutamate receptors, NMDA receptors require co-agonists such as glycine to bind to specific sites at the same time as glutamate binds, in order to be activated. Additionally, under resting conditions, magnesium ions block the channel pore of NMDA receptors. In order for the magnesium block to be removed, the membrane must be depolarized, which enables NMDA receptors to function as a detector for the coincidental presynaptic release of glutamate and postsynaptic depolarization, a process critical for computation of neuronal signals and for the establishment of certain forms of activitydependent synaptic plasticity. These unique properties place NMDA receptors in a position to regulate various neuronal functions, ranging from synaptic plasticity at a single synapse to complex cognitive functions such as learning andmemory.However, abnormal activation of NMDA receptors may also result in cellular dysfunction and contribute to the symptoms of many disorders of the nervous system. Therefore, the contribution of NMDA receptor abnormalities to the pathogenesis of several disorders will be discussed in the following sections, with a particular focus on progress made in the last decade.