Sensory experience and mTORC1 interplay orchestrates the maturation of cortical interneuron connectivity and tactile sensitivity

Clara A. Amegandjin, Maria-Isabel Carreño-Muñoz, Ruggiero Francavilla, Jorelle Linda Damo Kamda, M. Roussel, Antônia Sâmia Fernandes do Nascimento, Antoine Farley, Pegah Chehrazi, Alessandra Ciancone Chama, Bidisha Chattopadhyaya, Graziella Di Cristo

ABSTRACT Sensory abnormalities are core features of neurodevelopmental disorders, including autism. Although interneuron dysfunction is hypothesized to contribute to these deficits, the underlying mechanisms remain unclear. Here, we demonstrate that mTORC1 dysregulation in parvalbumin-expressing (PV) interneurons drives heightened tactile exploration and defensiveness. These behavioral changes coincide with whisker-evoked cortical responses characterized by increased power but degraded temporal precision. Excitatory inputs to PV cells, their intrinsic excitability and in vivo firing rate during tactile exploration are reduced, suggesting that mutant PV cells are hypoactive. Whisker trimming restricted to the third postnatal week prevented mTORC1 hyperactivation, PV cell input and output connectivity deficits as well as abnormal tactile cortical responses and behavior in adult mutant mice. Further, this manipulation rescued sociability deficits. Altogether, these data suggest that the interplay between mTORC1 signaling and sensory experience in PV cells regulates their connectivity, and contributes to the proper development of tactile and social behavior.