Early postnatal NMDA receptor ablation in cortical interneurons impairs affective state discrimination and social...

Emotion recognition is fundamental for effective social interactions among conspecifics. Impairments in affective state processing underlie several neuropsychiatric disorders, including schizophrenia, although the neurobiological substrate of these deficits remains unknown. We investigated the impact of early NMDA receptor hypofunction on socio-affective behaviors. Male mice lacking NMDA receptors in GABAergic interneurons of cerebral and hippocampal cortices from an early postnatal age (interNMDAr-KO mutants) were evaluated in affective state discrimination, social preference and social novelty preference, hierarchy and dominance, aggression and territoriality, and long-term social interaction. We show that interNMDAr-KO mice failed to discriminate conspecifics based on their affective states, unlike control littermates, while exhibiting an intact preference for social stimuli over inanimate objects. This discrimination deficit was observed regardless of whether affective valences were manipulated positively or negatively, via a palatable reward or social defeat, respectively. Additionally, interNMDAr-KO mice failed to establish a normal social hierarchy, consistently assuming subordinate roles against control littermates, and presented an abnormal response to conspecifics in the resident-intruder test. Finally, mice lacking NMDA receptors in GABAergic interneurons exhibited social withdrawal following exposure to unfamiliar conspecifics in a custom setting designed to monitor social behavior over extended time periods. This deficit was reversed by subchronic clozapine treatment. Our study thoroughly assessed the impact of a pathophysiological manipulation relevant to schizophrenia on social behavior in mice. Overall, this study provides evidence demonstrating that altered NMDAr-dependent development of cortical and hippocampal interneurons impairs affective state discrimination and leads to deficits in social functioning and long-term sociality.