NMDA Receptor

NMDA Receptor

NMDA receptor activity is important for synapse development, maintenance and plasticity, processes that underlie the cellular mechanisms involved in learning and memory. Improper regulation of NMDA receptor activity has harmful effects and is implicated in several neuropathologies.

Once identified as a specific class of ionotropic glutamate receptor, NMDA receptors immediately stood out as being unique due to their higher sensitivity to L-aspartate, as opposed to L-glutamate for the AMPA and kainite-type receptors. Later experiments showed L-glutamate was more effective at displacing APV, a potent NMDA antagonist, than L-aspartate, ultimately proving that glutamate was the neurotransmitter acting on NMDA receptors as well. Around this same time, NMDA receptors were proven to be unique in other ways among the excitatory glutamate receptors in that extracellular magnesium attenuated NMDA induced responses in a voltage-dependent manner and that glycine was required as a co-agonist.

NMDA receptors are unique in their high Ca2+ permeability, unitary conductance, and markedly slow gating kinetics. These characteristic properties lead to the slow, prolonged component of EPSCs at glutamatergic synapses that results in the bimodal Ca2+ influx into the postsynaptic neuron responsible for both neurological processes and diseases. NMDA deactivation kinetic rates, designated as the time course of channel closure upon removal of agonist, are tens and thousands of milliseconds whereas AMPA receptors deactivate in the millisecond range. Moreover, the GluN2 subunit dictates the current deactivation kinetics to a brief pre-synaptic release of glutamate (~1 ms at 1mM) with the GluN2A exhibiting the fastest deactivation kinetics, while the GluN2D has the slowest decay (τdecay: GluN2Ass/Ipk): ~0.3 - 0.6) with a seconds time scale; however, GluN2C- and GluN2D-containing receptors exhibit little desensitization.

It was originally thought that excitatory transmission in the central nervous system (CNS) was straightforward. Glutamate and its receptor were thought to be a streamlined system carrying information across the synaptic cleft much like the nicotinic acetylcholine receptor of the periphery. Unfortunately glutamatergic transmission was not so simple; many neurons in the central nervous system (CNS) contained all three classes of glutamate receptors making it initially unclear as to the role of each in synaptic transmission. However, it was found in the prototypical synapse of the cortex, spinal cord, neostriatum, and hippocampus that NMDA receptors co-localize with AMPA receptors to form the functional synaptic unit. Glutamate binds synaptic AMPA receptors triggering a brief, rapidly rising conductance that decays rapidly as a result of deactivation of the receptor. The rise time of the AMPA receptor mediated EPSC in the adult rat hippocampal CAl neuron has been measured to be between ~l-3ms with the decay time constant between 7-10ms. These values can vary and are dependent on the experimental preparation, recording method, subunit and splice variant composition, glutamate diffusion and clearance within the synaptic cleft, and temperature. NMDA receptors though co-activated with AMPA receptors by glutamate, contribute only a small and variable amount to the excitatory response at resting membrane potentials due to their voltage-dependent block by magnesium. Kainate receptors are also prevalent throughout the CNS, though their role in synaptic transmission is less clear. It has been shown that they can be important at both pre- and post-synaptic sites and are largely involved in development. The time course of their responses is slow and often only initiated after bursts of presynaptic activity possibly affecting coincidence detection and output timing at the specific circuits in which they are activated.


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