GABAB-mediated rescue of altered excitatory-inhibitory balance, gamma synchrony and behavioral deficits following constitutive NMDAR-hypofunction.
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.
Translational Neuroscience Program, Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA.
M J
MJ
Gandal
J
J
Sisti
K
K
Klook
P I
PI
Ortinski
V
V
Leitman
Y
Y
Liang
T
T
Thieu
R
R
Anderson
R C
RC
Pierce
G
G
Jonak
R E
RE
Gur
G
G
Carlson
S J
SJ
Siegel
D000818:Animals; D001321:Autistic Disorder / Q000503:physiopathology; D001418:Baclofen / Q000494:pharmacology*; D004195:Disease Models, Animal; D005072:Evoked Potentials, Auditory / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology*; D005464:Fluorobenzenes / Q000494:pharmacology; D058786:GABA-B Receptor Agonists / Q000494:pharmacology*; D017403:In Situ Hybridization; D008607:Intellectual Disability / Q000503:physiopathology; D007395:Interneurons / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010320:Parvalbumins / Q000378:metabolism; D010641:Phenotype; D017966:Pyramidal Cells / Q000378:metabolism / Q000473:pathology; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics* / Q000378:metabolism; D018967:Risperidone / Q000494:pharmacology; D012559:Schizophrenia / Q000503:physiopathology; D012919:Social Behavior; D055366:Synaptic Potentials / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D014230:Triazoles / Q000494:pharmacology
D005464:Fluorobenzenes; D058786:GABA-B Receptor Agonists; D010320:Parvalbumins; D016194:Receptors, N-Methyl-D-Aspartate; D014230:Triazoles; C409903:L 838,417; D001418:Baclofen; D018967:Risperidone