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.
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Acknowledgements
We thank N. Heintz for pLD53.SCAEB plasmid and the BAC homologous recombination protocol, F. Costantini for the loxP-flanked Rosa26-EYFP mouse strain, D.L. Brautigan for antibody to Ppp1r2, B. Condie and J. Rubenstein for Gad67 cDNA, J. Pickel for oocyte injections, J.N. Crawley for advice on behavioral testing, S. Zhang, J. Okolonta and M. Taylor for technical and animal care assistance, H. Matsunami for in situ hybridization protocol, Y. Kubota for immunostaining protocol and J. Yamamoto for Neuralynx/Xclust2 conversion software. We thank D.R. Weinberger, M.M. Behrens, G. Kunos, I. Henter, K.M. Christian, H. Giesen and H.A. Nash for critical comments on the manuscript. We also acknowledge the CURE/Digestive diseases research center at the University of California Los Angeles and the US National Institute of Mental Health Chemical Synthesis and Drug Supply Program for antibodies and risperidone, respectively. This work was supported by the Intramural Research Program of the US National Institute of Mental Health and of the US National Institute on Alcohol Abuse and Addiction.
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J.E.B. and K.N. designed most of the experiments and wrote the paper. V.Z. was responsible for the slice physiology data. E.R.S. and Z.J. conducted some of the behavioral testing. G.Y. and E.M.Q. were responsible for the visually evoked potentials. Y.L. provided animal resources. All other experiments were data-collected by J.E.B. All authors discussed the results and commented on the manuscript.
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Belforte, J., Zsiros, V., Sklar, E. et al. Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes. Nat Neurosci 13, 76–83 (2010). https://doi.org/10.1038/nn.2447
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DOI: https://doi.org/10.1038/nn.2447
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