Mar 30, 2020

Inhibition of mTOR during a postnatal sensitive window rescues deficits in GABAergic PV cell connectivity and social behavior caused by loss of TSC1.

BioRxiv : the Preprint Server for Biology
Franco CaudaGraziella Di Cristo

Abstract

Mutations in regulators of the Mechanistic Target Of Rapamycin Complex 1 (mTORC1), such as Tsc1/2, lead to neurodevelopmental disorders associated with autism, intellectual disabilities and epilepsy. Whereas the effects of mTORC1 signaling dysfunction within diverse cell types are likely critical for the onset of the diverse neurological symptoms associated with mutations in mTORC1 regulators, they are not well understood. In particular, the effects of mTORC1 dys-regulation in specific types of inhibitory interneurons are unclear. Here, we showed that Tsc1 haploinsufficiency in parvalbumin (PV)-positive GABAergic interneurons either in cortical organotypic cultures or in vivo caused a premature increase in their perisomatic innervations, followed by a striking loss in adult mice. This effects were accompanied by alterations of AMPK-dependent autophagy in pre-adolescent but not adult mice. PV cell-restricted Tsc1 mutant mice showed deficits in social behavior. Treatment with the mTOR inhibitor Rapamycin restricted to the third postnatal week was sufficient to permanently rescue deficits in both PV cell innervation and social behavior in adult conditional haploinsufficient mice. All together, these findings identify a novel role ...Continue Reading

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Mentioned in this Paper

Brain Injuries
Patterns
Inferior
Meta-Analysis (Publications)
Meta Analysis (Statistical Procedure)
Trees (plant)
Schizophrenia
Tissue Damage
Brain
Gray Matter

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