Differential role of NR2A and NR2B subunits in N-methyl-D-aspartate receptor antagonist-induced aberrant cortical gamma oscillations

Biol Psychiatry. 2012 Jun 1;71(11):987-95. doi: 10.1016/j.biopsych.2011.10.002. Epub 2011 Nov 4.

Abstract

Background: N-methyl-D-aspartate receptor (NMDA-R) hypofunction plays an important role in cognitive impairment in schizophrenia. NMDA-R antagonists elicit psychotic symptoms in humans and schizophrenia-relevant signs in rodents, including a strong increase in cortical gamma activity. NMDA-Rs are composed of different subunits, and accumulating evidence indicates that neuronal damage due to NMDA-R antagonists depends on their action on a specific type of the receptor containing the NR2A subunit. In human schizophrenics, NR2A is selectively reduced in fast-firing interneurons. These neurons are critical for gamma oscillations, indicating that pathological changes in gamma activity may depend on subunit-specific NMDA-R deficit. The present study tested this hypothesis.

Methods: Cortical electroencephalograms were recorded in freely moving rats and the changes in gamma power were measured after administration of NMDA-R antagonists with different subunit selectivity, including NR2A-preferring (PEAQX, n = 5; NVP-AAM077, n = 18), NR2B-selective (ifenprodil, n = 6; threo-ifenprodil, n = 4; Ro25-6985, n = 13), and NR2C/D-selective (n = 8) antagonists, along with vehicle and nonselective NMDA-R antagonists (ketamine, n = 10; MK801, n = 12). Changes in prepulse inhibition of startle was tested after MK-801 (n = 6), NVP-AAM077, and Ro-6891 (n = 5) injection.

Results: Strong increase in gamma power was induced by nonselective NMDA-R antagonists and by blockade of NMDA-Rs containing the NR2A subunit, with co-occurring gating deficits and diminished low-frequency modulation of gamma oscillations. In contrast, selective blockade of NR2B, C, or D subunit-containing receptors had minor effects.

Conclusions: Major subtype-specific differences in the role of NMDA-Rs in cortical gamma oscillation may have implications for the pathomechanism and treatment of cognitive impairment in schizophrenia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Waves / drug effects
  • Brain Waves / physiology*
  • Cognition Disorders
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Neurons / physiology
  • Rats
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / physiology*
  • Reflex, Startle / drug effects
  • Reflex, Startle / physiology*
  • Schizophrenia / physiopathology*

Substances

  • Excitatory Amino Acid Antagonists
  • NR2B NMDA receptor
  • NR2C NMDA receptor
  • NR2D NMDA receptor
  • Receptors, N-Methyl-D-Aspartate
  • N-methyl D-aspartate receptor subtype 2A