title: Differential role of NR2A and NR2B subunits in N-methyl-D-aspartate receptor antagonist-induced aberrant cortical gamma oscillations.
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.
authors: Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts MA02215, USA. bkocsis@hms.harvard.edu
authors: Bernat
authors: B
authors: Kocsis
mesh_terms: D000818:Animals; D058256:Brain Waves / Q000187:drug effects / Q000502:physiology*; D003072:Cognition Disorders; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D009474:Neurons / Q000502:physiology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology*; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology*; D012559:Schizophrenia / Q000503:physiopathology*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; C121001:NR2B NMDA receptor; C432823:NR2C NMDA receptor; C464436:NR2D NMDA receptor