Triheteromeric NMDA receptors at hippocampal synapses

Kenneth R. Tovar, Matthew J. McGinley, Gary L. Westbrook

Research output: Contribution to journalArticle

112 Scopus citations

Abstract

NMDA receptors are composed of two GluN1 (N1) and two GluN2 (N2) subunits. Constituent N2 subunits control the pharmacological and kinetic characteristics of the receptor. NMDA receptors in hippocampal or cortical neurons are often thought of as diheteromeric, meaning that they contain only one type of N2 subunit. However, triheteromeric receptors with more than one type of N2 subunit also have been reported, and the relative contribution of diheteromeric and triheteromeric NMDA receptors at synapses has been difficult to assess. Because wild-type hippocampal principal neurons express N1, N2A, and N2B, we used cultured hippocampal principal neurons from N2A and N2B knock-out mice as templates for diheteromeric synaptic receptors. However, summation of N1/N2B and N1/N2A EPSCs could not account for the deactivation kinetics of wild-type EPSCs. To make a quantitative estimate of NMDA receptor subtypes at wild-type synapses, we used the deactivation kinetics and the effects of the competitive antagonist NVP-AAM077. Our results indicate that three types of NMDA receptors contribute to wild-type EPSCs, with at least two-thirds being triheteromeric receptors. Functional isolation of synaptic triheteromeric receptors revealed deactivation kinetics and pharmacology that were distinct from either diheteromeric receptor subtype. Because of differences in open probability, synaptic triheteromeric receptors outnumbered N1/N2A receptors by 5.8 to 1 and N1/N2B receptors by 3.2 to 1. Our results suggest that triheteromeric NMDA receptors must either be preferentially assembled or preferentially localized at synapses.

Original languageEnglish (US)
Pages (from-to)9150-9160
Number of pages11
JournalJournal of Neuroscience
Volume33
Issue number21
DOIs
StatePublished - May 22 2013

ASJC Scopus subject areas

  • Neuroscience(all)

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