TY - JOUR
T1 - GABA B -mediated rescue of altered excitatory-inhibitory balance, gamma synchrony and behavioral deficits following constitutive NMDAR-hypofunction
AU - Gandal, M. J.
AU - Sisti, J.
AU - Klook, K.
AU - Ortinski, P. I.
AU - Leitman, V.
AU - Liang, Y.
AU - Thieu, T.
AU - Anderson, R.
AU - Pierce, R. C.
AU - Jonak, G.
AU - Gur, R. E.
AU - Carlson, G.
AU - Siegel, S. J.
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
KW - GABAergic signaling
KW - NMDA-receptor
KW - animal model
KW - gamma oscillation
KW - neuropsychiatric disease
UR - http://www.scopus.com/inward/record.url?scp=84866106557&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84866106557&partnerID=8YFLogxK
U2 - 10.1038/tp.2012.69
DO - 10.1038/tp.2012.69
M3 - Article
C2 - 22806213
AN - SCOPUS:84866106557
SN - 2158-3188
VL - 2
JO - Translational Psychiatry
JF - Translational Psychiatry
M1 - e142
ER -
