Forebrain GABAergic cell-selective genetic manipulation in mice

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In this transgenic line developed by Juan Belforte et al, genetic elimination of the NMDARs begins at postnatal day 7 and is targeted to 50% of cortical and hippocampal GABAergic cells, primarily parvalbumin positive ones. Veronika Zsiros showed an absence of NMDA receptor channel currents in virtually all of the targeted cells by whole-cell patch-clamp recordings thus confirming via electrophysiology the functional knockout of this receptor. We then conducted an extensive battery of behavioral tests and found that the mutants exhibited a variety of psychiatric disease-like phenotypes. Early postnatal modification of inhibitory networks in this mouse model revealed psychomotor agitation, sensorimotor deficits, anhedonic behavior, anxiety-like behavior, and deficits in nesting and mating. In addition, we addressed cognitive impairments in learning-related tasks and found deficits in spatial working memory and short-term social memory. Notably, the working memory deficit was ameliorated by the antipsychotic drug, risperidone. We also observed an exacerbation of some mutant phenotypes following social isolation stress which may serve as a model for stress-induced precipitation of human psychiatric disorders. Interestingly, when NR1 was genetically ablated in the same population of cells after adolescence using a different strain, we observed no such behavioral phenotypes as described above, suggesting that early postnatal NR1 ablation is critical for the development of psychiatric disease-like behavior. These findings strongly support the notion that loss of NMDAR activity in cortical GABAergic interneurons during the early postnatal period leads to psychiatric disorder-like behavior. To identify how dysfunction of cortical inhibitory networks is manifest at the cellular level, we are now conducting electrophysiological recordings from freely moving animals. Through the development of this novel genetic system, we have been able to target a widely distributed neural network and demonstrate that perturbations of this system may play a causal role in the onset of neuropsychiatric disorders.