GABA B -mediated rescue of altered excitatory-inhibitory balance, gamma synchrony and behavioral deficits following constitutive NMDAR-hypofunction

M. J. Gandal, J. Sisti, K. Klook, P. I. Ortinski, V. Leitman, Y. Liang, T. Thieu, R. Anderson, R. C. Pierce, G. Jonak, R. E. Gur, G. Carlson, S. J. Siegel

Research output: Contribution to journalArticlepeer-review

109 Scopus citations

Abstract

Reduced N-methyl-D-aspartate-receptor (NMDAR) signaling has been associated with schizophrenia, autism and intellectual disability. NMDAR-hypofunction is thought to contribute to social, cognitive and gamma (30-80 Hz) oscillatory abnormalities, phenotypes common to these disorders. However, circuit-level mechanisms underlying such deficits remain unclear. This study investigated the relationship between gamma synchrony, excitatory-inhibitory (E/I) signaling, and behavioral phenotypes in NMDA-NR1 neo/ mice, which have constitutively reduced expression of the obligate NR1 subunit to model disrupted developmental NMDAR function. Constitutive NMDAR-hypofunction caused a loss of E/I balance, with an increase in intrinsic pyramidal cell excitability and a selective disruption of parvalbumin-expressing interneurons. Disrupted E/I coupling was associated with deficits in auditory-evoked gamma signal-to-noise ratio (SNR). Gamma-band abnormalities predicted deficits in spatial working memory and social preference, linking cellular changes in E/I signaling to target behaviors. The GABA B -receptor agonist baclofen improved E/I balance, gamma-SNR and broadly reversed behavioral deficits. These data demonstrate a clinically relevant, highly translatable neural-activity-based biomarker for preclinical screening and therapeutic development across a broad range of disorders that share common endophenotypes and disrupted NMDA-receptor signaling.

Original languageEnglish (US)
Article numbere142
JournalTranslational psychiatry
Volume2
DOIs
StatePublished - 2012
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Biological Psychiatry

Keywords

  • GABAergic signaling
  • NMDA-receptor
  • animal model
  • gamma oscillation
  • neuropsychiatric disease

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