Sensitive period for rescuing parvalbumin interneurons connectivity and social behavior deficits caused by TSC1 loss

The Mechanistic Target Of Rapamycin Complex 1 (mTORC1) pathway controls several aspects of neuronal development. Mutations in regulators of mTORC1, such as Tsc1 and Tsc2, lead to neurodevelopmental disorders associated with autism, intellectual disabilities and epilepsy. The correct development of inhibitory interneurons is crucial for functional circuits. In particular, the axonal arborisation and synapse density of parvalbumin (PV)-positive GABAergic interneurons change in the postnatal brain. How and whether mTORC1 signaling affects PV cell development is unknown. Here, we show that Tsc1 haploinsufficiency causes a premature increase in terminal axonal branching and bouton density formed by mutant PV cells, followed by a loss of perisomatic innervation in adult mice. PV cell-restricted Tsc1 haploinsufficient and knockout mice show deficits in social behavior. Finally, we identify a sensitive period during the third postnatal week during which treatment with the mTOR inhibitor Rapamycin rescues deficits in both PV cell innervation and social behavior in adult conditional haploinsufficient mice. Our findings reveal a role of mTORC1 signaling in the regulation of the developmental time course and maintenance of cortical PV cell connectivity and support a mechanistic basis for the targeted rescue of autism-related behaviors in disorders associated with deregulated mTORC1 signaling. Regulators of mTORC1, such as Tsc1, are involved in neurodevelopmental disorders associated with autism, intellectual disabilities and epilepsy. The authors identify a role of mTORC1 signaling in the regulation and maintenance of cortical parvalbumin cell connectivity and social behaviour.

Automated summary

Regulators of mTORC1, such as Tsc1, play a significant role in neurodevelopmental disorders associated with autism, intellectual disabilities, and epilepsy. The mTORC1 signaling pathway is essential for regulating and maintaining cortical parvalbumin cell connectivity and social behavior.