Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes

By J. Belforte, V. Zsiros, Elyse R. Sklar, Zhihong Jiang, G.-Z. Yu, Yuqing Li, E. Quinlan, K. Nakazawa. Nature Neuroscience, 2009

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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.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/41038bc5f0ffd8df6e3c0bc732a704ffdc73d49a

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Citations in the corpus

Hilar Mossy Cell Degeneration Causes Transient Dentate Granule Cell Hyperexcitability and Impaired Pattern Separation (2012, positive): “Slice Physiology Whole-cell recordings were made from dentate granule cells of the mutant mouse line and their littermates (aged 12–20 weeks) under an upright microscope with DIC/infrared/fluorescence optics (Olympus) as described in Belforte et al. (2010).”
Neurophysiological and Computational Principles of Cortical Rhythms in Cognition (2010, background): “Fourth, NMDA hypofunction leads to a selective reduction of the excitatory drive for a subpopulation of interneurons (72, 389, 582, 1024); one of the consequences could be abnormal inhibition-dependent synchronous oscillations (593, 633, 818).”
Interneuron dysfunction in psychiatric disorders (2012, result): “Moreover, conditional deletion of the gene encoding the NR1 subunit of NMDA receptors from PV + interneurons in mice leads to disinhibition of excitatory pyramidal cells, a reduction in neuronal synchrony and, ultimately, the emergence of schizophrenia-like symptoms that are similar to those descri”