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

Clara A Amegandjin,Armen Saghatelyan,Martin Berryer,Mayukh Choudhury,Bidisha Chattopadhyaya,Ariane Quintal,Josianne Nunes Carriço,Marina Snapyan,Vidya Jadhav,Graziella Di Cristo

doi:10.1038/s41467-021-23939-7

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.

Highlights

The Mechanistic Target Of Rapamycin Complex 1 pathway controls several aspects of neuronal development
To investigate whether Mechanistic Target Of Rapamycin Complex 1 (mTORC1) activation plays a role in this process, we first analyzed the time course of pS6 expression, one of the direct downstream effectors of mTORC1, in PV cells identified by PV immunolabeling (Fig. 1a)
At EP18, before the peak of PV cell synapse proliferation, similar to what we observed with the single cell Tsc[1] deletion, we found that PV cells from both Tg(Nkx2.1-Cre); Tsc1flox/flox and Tg(Nkx2.1-Cre);Tsc1flox/+ mice formed more complex perisomatic innervations, characterized by increased perisomatic bouton density (Fig. 4a–d) and terminal branching (Fig. 4e) compared to age-matched control PV cells in cultures transfected from Tsc1Ctrl mice

Summary

Introduction

The Mechanistic Target Of Rapamycin Complex 1 (mTORC1) pathway controls several aspects of neuronal development. Since mutations in Tsc[1] give rise to autistic traits, we questioned whether and how Tsc[1] deletion selectively in PV cells affects their connectivity, and whether and to what extent these alterations in cortical PV cell circuits might be contributing to changes in social behavior downstream of altered mTOR signaling. Conditional mutant mice showed social behavior deficits Both PV cell connectivity and social behavior in adult mice were rescued by a short treatment with the mTORC1 inhibitor rapamycin during the third postnatal week, suggesting that inhibiting the premature maturation of PV cell innervations was sufficient to ameliorate the long-term neurological outcomes of the mutation

Methods

Results

Conclusion