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

Neuropsychopharmacology volume 50, pages 1119–1129 (2025)Cite this article

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Abstract

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.

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Fig. 1: Early NMDAr ablation in cortical interneurons leads to deficits in affective state discrimination.
Fig. 2: Discrimination deficits in interNMDAr-KO mice extend to different affective valences.
Fig. 3: Affective state discrimination deficits in interNMDAr-KO mice are not due to a general impairment in social behavior.
Fig. 4: Early postnatal NMDAr ablation leads to maladaptive functioning in different social contexts.
Fig. 5: InterNMDAr-KO mice display social withdrawal after extended peer interaction, which is reversed by subchronic treatment with clozapine.

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Acknowledgements

We thank Camila Zold, Noelia Weisstaub, and Amaicha Depino for their critical reading of the manuscript; Analia Lopez Diaz, Agostina Presta, Veronica Risso, Lucia Garbini, Andres Varani, and Micaela Buscema for technical assistance, and the GNS group for feedback on previous drafts. Illustrations were created with BioRender. We also thank the Rospaw Laboratory for their kind donation of clozapine.

Funding

This work was supported in part by Agencia Nacional de Promoción Científica y Tecnológica, Proyectos de Investigación Científicos y Tecnológicos PICT 2019-3626 [EPB], 2018-0581 and 2021-00324 [JEB]; Universidad de Buenos Aires, UBACYT 20020220300072BA [EPB, JEB]; Brain and Behavior Research Foundation, NARSAD Young Investigator Grant Award 2015-#23983 [EPB]; Pew Charitable Trusts Repatriation Grant [EPB]; Fundación Bunge y Born - Fundación Williams, Mario Hirsch Award [EPB]. All authors were supported by the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) and the Universidad de Buenos Aires, Argentina.

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  1. These authors contributed equally: Estefanía P. Bello, Juan E. Belforte.

Authors and Affiliations

  1. Grupo de Neurociencia de Sistemas, Departamento de Ciencias Fisiológicas, Facultad de Ciencias Médicas, Universidad de Buenos Aires, Buenos Aires, Argentina

    Juan M. Uehara, Martina Gomez Acosta, Estefanía P. Bello & Juan E. Belforte

  2. Instituto de Fisiología y Biofísica Bernardo Houssay (IFIBIO-Houssay), UBA-CONICET, Buenos Aires, Argentina

    Juan M. Uehara, Martina Gomez Acosta, Estefanía P. Bello & Juan E. Belforte

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Contributions

JMU, EPB & JEB designed the study. JMU & MGA performed the experiments and collected data. JMU, MGA, EPB & JEB analyzed the data. JMU, EPB & JEB wrote the manuscript. JMU, MGA, EPB & JEB reviewed and edited the manuscript.

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Correspondence to Estefanía P. Bello or Juan E. Belforte.

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Uehara, J.M., Gomez Acosta, M., Bello, E.P. et al. Early postnatal NMDA receptor ablation in cortical interneurons impairs affective state discrimination and social functioning. Neuropsychopharmacol. 50, 1119–1129 (2025). https://doi.org/10.1038/s41386-025-02051-0

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