Abstract
Cortical GABAergic dysfunction may underlie the pathophysiology of psychiatric disorders, including schizophrenia. Here, we characterized a mouse strain in which the essential NR1 subunit of the NMDA receptor (NMDAR) was selectively eliminated in 40-50% of cortical and hippocampal interneurons in early postnatal development. Consistent with the NMDAR hypofunction theory of schizophrenia, distinct schizophrenia-related symptoms emerged after adolescence, including novelty-induced hyperlocomotion, mating and nest-building deficits, as well as anhedonia-like and anxiety-like behaviors. Many of these behaviors were exacerbated by social isolation stress. Social memory, spatial working memory and prepulse inhibition were also impaired. Reduced expression of glutamic acid decarboxylase 67 and parvalbumin was accompanied by disinhibition of cortical excitatory neurons and reduced neuronal synchrony. Postadolescent deletion of NR1 did not result in such abnormalities. These findings suggest that early postnatal inhibition of NMDAR activity in corticolimbic GABAergic interneurons contributes to the pathophysiology of schizophrenia-related disorders.
Publication types
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Research Support, N.I.H., Intramural
MeSH terms
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Action Potentials / genetics
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Analysis of Variance
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Animals
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Animals, Newborn
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Cerebral Cortex / pathology*
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Disease Models, Animal
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Exploratory Behavior / physiology
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Gene Expression Regulation, Developmental / genetics
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Glutamate Decarboxylase / genetics
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Glutamate Decarboxylase / metabolism
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Hyperkinesis / etiology
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Hyperkinesis / genetics
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Interneurons / physiology*
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Limbic System / pathology*
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Memory Disorders / etiology
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Memory Disorders / genetics
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Mutation / genetics
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Neural Pathways / pathology
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Parvalbumins / genetics
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Parvalbumins / metabolism
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Proteins / genetics
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RNA, Messenger / metabolism
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Receptors, N-Methyl-D-Aspartate / deficiency*
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Recognition, Psychology / physiology
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Schizophrenia* / genetics
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Schizophrenia* / pathology
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Schizophrenia* / physiopathology
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Social Isolation / psychology
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Statistics, Nonparametric
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gamma-Aminobutyric Acid / metabolism
Substances
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NR1 NMDA receptor
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Parvalbumins
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Proteins
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RNA, Messenger
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Receptors, N-Methyl-D-Aspartate
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protein phosphatase inhibitor-2
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gamma-Aminobutyric Acid
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Glutamate Decarboxylase
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glutamate decarboxylase 1