NMDA receptor subunits: diversity, development and disease

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Abstract

<p class="first" id="d7589e51">Current Opinion in Neurobiology, 11(3), 327-335</p>

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Developmental and regional expression in the rat brain and functional properties of four NMDA receptors.

H Monyer, N. Burnashev, D Laurie … (1994)

An in situ study of mRNAs encoding NMDA receptor subunits in the developing rat CNS revealed that, at all stages, the NR1 gene is expressed in virtually all neurons, whereas the four NR2 transcripts display distinct expression patterns. NR2B and NR2D mRNAs occur prenatally, whereas NR2A and NR2C mRNAs are first detected near birth. All transcripts except NR2D peak around P20. NR2D mRNA, present mainly in midbrain structures, peaks around P7 and thereafter decreases to adult levels. Postnatally, NR2B and NR2C transcript levels change in opposite directions in the cerebellar internal granule cell layer. In the adult hippocampus, NR2A and NR2B mRNAs are prominent in CA1 and CA3 pyramidal cells, but NR2C and NR2D mRNAs occur in different subsets of interneurons. Recombinant binary NR1-NR2 channels show comparable Ca2+ permeabilities, but marked differences in voltage-dependent Mg2+ block and in offset decay time constants. Thus, the distinct expression profiles and functional properties of NR2 subunits provide a basis for NMDA channel heterogeneity in the brain.

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Changing subunit composition of heteromeric NMDA receptors during development of rat cortex.

M. Sheng, J. Cummings, L A Roldan … (1994)

Activation of the N-methyl-D-aspartate (NMDA) receptor is important for certain forms of activity-dependent synaptic plasticity, such as long-term potentiation (reviewed in ref. 1), and the patterning of connections during development of the visual system (reviewed in refs 2, 3). Several subunits of the NMDA receptor have been cloned: these are NMDAR1 (NR1), and NMDAR2A, 2B, 2C and 2D (NR2A-D). Based on heterologous co-expression studies, it is inferred that NR1 encodes an essential subunit of NMDA receptors and that functional diversity of NMDA receptors in vivo is effected by differential incorporation of subunits NR2A-NR2D. Little is known, however, about the actual subunit composition or heterogeneity of NMDA receptors in the brain. By co-immunoprecipitation with subunit-specific antibodies, we present here direct evidence that NMDA receptors exist in rat neocortex as heteromeric complexes of considerable heterogeneity, some containing both NR2A and NR2B subunits. A progressive alteration in subunit composition seen postnatally could contribute to NMDA-receptor variation and changing synaptic plasticity during cortical development.

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Mice with reduced NMDA receptor expression display behaviors related to schizophrenia.

Amy Mohn, Raul Gainetdinov, Marc G. Caron … (1999)

N-methyl-D-aspartate receptors (NMDARs) represent a subclass of glutamate receptors that play a critical role in neuronal development and physiology. We report here the generation of mice expressing only 5% of normal levels of the essential NMDAR1 (NR1) subunit. Unlike NR1 null mice, these mice survive to adulthood and display behavioral abnormalities, including increased motor activity and stereotypy and deficits in social and sexual interactions. These behavioral alterations are similar to those observed in pharmacologically induced animal models of schizophrenia and can be ameliorated by treatment with haloperidol or clozapine, antipsychotic drugs that antagonize dopaminergic and serotonergic receptors. These findings support a model in which reduced NMDA receptor activity results in schizophrenic-like behavior and reveals how pharmacological manipulation of monoaminergic pathways can affect this phenotype.