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

Clara A. Amegandjin, Mayukh Choudhury, Vidya Jadhav, Josianne Nunes Carriço, Ariane Quintal, Martin Berryer, Marina Snapyan, Bidisha Chattopadhyaya, Armen Saghatelyan and Graziella Cristo ()
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Clara A. Amegandjin: Neurosciences Department, Université de Montréal, Pavillon Paul-G.-Desmarais
Mayukh Choudhury: Neurosciences Department, Université de Montréal, Pavillon Paul-G.-Desmarais
Vidya Jadhav: Neurosciences Department, Université de Montréal, Pavillon Paul-G.-Desmarais
Josianne Nunes Carriço: Centre de Recherche, CHU Sainte-Justine (CHUSJ)
Ariane Quintal: Neurosciences Department, Université de Montréal, Pavillon Paul-G.-Desmarais
Martin Berryer: Neurosciences Department, Université de Montréal, Pavillon Paul-G.-Desmarais
Marina Snapyan: CERVO Brain Research Center
Bidisha Chattopadhyaya: Centre de Recherche, CHU Sainte-Justine (CHUSJ)
Armen Saghatelyan: CERVO Brain Research Center
Graziella Cristo: Neurosciences Department, Université de Montréal, Pavillon Paul-G.-Desmarais

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-23939-7

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