PMID- 22806213
OWN - NLM
STAT- MEDLINE
DCOM- 20130314
LR  - 20211021
IS  - 2158-3188 (Electronic)
IS  - 2158-3188 (Linking)
VI  - 2
IP  - 7
DP  - 2012 Jul 17
TI  - GABAB-mediated rescue of altered excitatory-inhibitory balance, gamma synchrony 
      and behavioral deficits following constitutive NMDAR-hypofunction.
PG  - e142
LID - 10.1038/tp.2012.69 [doi]
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.
FAU - Gandal, M J
AU  - Gandal MJ
AD  - Translational Neuroscience Program, Department of Psychiatry, University of 
      Pennsylvania, Philadelphia, PA 19104, USA.
FAU - Sisti, J
AU  - Sisti J
FAU - Klook, K
AU  - Klook K
FAU - Ortinski, P I
AU  - Ortinski PI
FAU - Leitman, V
AU  - Leitman V
FAU - Liang, Y
AU  - Liang Y
FAU - Thieu, T
AU  - Thieu T
FAU - Anderson, R
AU  - Anderson R
FAU - Pierce, R C
AU  - Pierce RC
FAU - Jonak, G
AU  - Jonak G
FAU - Gur, R E
AU  - Gur RE
FAU - Carlson, G
AU  - Carlson G
FAU - Siegel, S J
AU  - Siegel SJ
LA  - eng
GR  - K01 DA031747/DA/NIDA NIH HHS/United States
PT  - Journal Article
DEP - 20120717
PL  - United States
TA  - Transl Psychiatry
JT  - Translational psychiatry
JID - 101562664
RN  - 0 (Fluorobenzenes)
RN  - 0 (GABA-B Receptor Agonists)
RN  - 0 (Parvalbumins)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 0 (Triazoles)
RN  - 8CZO0970G3 (L 838,417)
RN  - H789N3FKE8 (Baclofen)
RN  - L6UH7ZF8HC (Risperidone)
SB  - IM
MH  - Animals
MH  - Autistic Disorder/physiopathology
MH  - Baclofen/*pharmacology
MH  - Disease Models, Animal
MH  - Evoked Potentials, Auditory/drug effects/*genetics/physiology
MH  - Exploratory Behavior/drug effects/*physiology
MH  - Fluorobenzenes/pharmacology
MH  - GABA-B Receptor Agonists/*pharmacology
MH  - In Situ Hybridization
MH  - Intellectual Disability/physiopathology
MH  - Interneurons/metabolism/pathology
MH  - Male
MH  - Mice
MH  - Mice, Transgenic
MH  - Parvalbumins/metabolism
MH  - Phenotype
MH  - Pyramidal Cells/metabolism/pathology
MH  - Receptors, N-Methyl-D-Aspartate/*genetics/metabolism
MH  - Risperidone/pharmacology
MH  - Schizophrenia/physiopathology
MH  - *Social Behavior
MH  - Synaptic Potentials/drug effects/*genetics/physiology
MH  - Triazoles/pharmacology
PMC - PMC3410621
EDAT- 2012/07/19 06:00
MHDA- 2013/03/15 06:00
PMCR- 2012/07/01
CRDT- 2012/07/19 06:00
PHST- 2012/07/19 06:00 [entrez]
PHST- 2012/07/19 06:00 [pubmed]
PHST- 2013/03/15 06:00 [medline]
PHST- 2012/07/01 00:00 [pmc-release]
AID - tp201269 [pii]
AID - 10.1038/tp.2012.69 [doi]
PST - epublish
SO  - Transl Psychiatry. 2012 Jul 17;2(7):e142. doi: 10.1038/tp.2012.69.