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

Transl Psychiatry. 2012 Jul 17;2(7):e142. doi: 10.1038/tp.2012.69.

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.

MeSH terms

  • Animals
  • Autistic Disorder / physiopathology
  • Baclofen / pharmacology*
  • Disease Models, Animal
  • Evoked Potentials, Auditory / drug effects
  • Evoked Potentials, Auditory / genetics*
  • Evoked Potentials, Auditory / physiology
  • Exploratory Behavior / drug effects
  • Exploratory Behavior / physiology*
  • Fluorobenzenes / pharmacology
  • GABA-B Receptor Agonists / pharmacology*
  • In Situ Hybridization
  • Intellectual Disability / physiopathology
  • Interneurons / metabolism
  • Interneurons / pathology
  • Male
  • Mice
  • Mice, Transgenic
  • Parvalbumins / metabolism
  • Phenotype
  • Pyramidal Cells / metabolism
  • Pyramidal Cells / pathology
  • Receptors, N-Methyl-D-Aspartate / genetics*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Risperidone / pharmacology
  • Schizophrenia / physiopathology
  • Social Behavior*
  • Synaptic Potentials / drug effects
  • Synaptic Potentials / genetics*
  • Synaptic Potentials / physiology
  • Triazoles / pharmacology

Substances

  • Fluorobenzenes
  • GABA-B Receptor Agonists
  • Parvalbumins
  • Receptors, N-Methyl-D-Aspartate
  • Triazoles
  • L 838,417
  • Baclofen
  • Risperidone