Subunit-specific NMDAR antagonism dissociates schizophrenia subtype-relevant oscillopathies associated with frontal hypofunction and hippocampal hyperfunction

Sci Rep. 2018 Aug 2;8(1):11588. doi: 10.1038/s41598-018-29331-8.

Abstract

NMDAR antagonism alters mesolimbic, hippocampal, and cortical function, acutely reproducing the positive, cognitive, and negative symptoms of schizophrenia. These physiological and behavioral effects may depend differentially on NMDAR subtype- and region-specific effects. The dramatic electrophysiological signatures of NMDAR blockade in rodents include potentiated high frequency oscillations (HFOs, ∼140 Hz), likely generated in mesolimbic structures, and increased HFO phase-amplitude coupling (PAC), a phenomenon related to goal-directed behavior and dopaminergic tone. This study examined the impact of subtype-specific NMDAR antagonism on HFOs and PAC. We found that positive-symptom-associated NR2A-preferring antagonism (NVP-AAM077), but not NR2B-specific antagonism (Ro25-6985) or saline control, replicated increases in HFO power seen with nonspecific antagonism (MK-801). However, PAC following NR2A-preferring antagonism was distinct from all other conditions. While θ-HFO PAC was prominent or potentiated in other conditions, NVP-AAM077 increased δ-HFO PAC and decreased θ-HFO PAC. Furthermore, active wake epochs exhibiting narrowband frontal δ oscillations, and not broadband sleep-associated δ, selectively exhibited δ-HFO coupling, while paradoxical sleep epochs having a high CA1 θ to frontal δ ratio selectively exhibited θ-HFO coupling. Our results suggest: (1) NR2A-preferring antagonism induces oscillopathies reflecting frontal hyperfunction and hippocampal hypofunction; and (2) HFO PAC indexes cortical vs. hippocampal control of mesolimbic circuits.

Publication types

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

MeSH terms

  • Animals
  • Frontal Lobe* / metabolism
  • Frontal Lobe* / pathology
  • Frontal Lobe* / physiopathology
  • Hippocampus* / metabolism
  • Hippocampus* / pathology
  • Hippocampus* / physiopathology
  • Quinoxalines / pharmacology*
  • Rats
  • Receptors, N-Methyl-D-Aspartate* / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate* / metabolism
  • Schizophrenia* / metabolism
  • Schizophrenia* / pathology
  • Schizophrenia* / physiopathology
  • Theta Rhythm / drug effects*

Substances

  • 5-(alpha-methyl-4-bromobenzylamino)phosphonomethyl-1,4-dihydroquinoxaline-2,3-dione
  • NR2B NMDA receptor
  • Quinoxalines
  • Receptors, N-Methyl-D-Aspartate
  • N-methyl D-aspartate receptor subtype 2A