Tsc1-mTORC1 signaling controls striatal dopamine release and cognitive flexibility

Polina Kosillo,Helen S Bateup,Kamran M Ahmed,Natalie M Doig,Sarah Threlfell,Lisa Conyers,Peter J Magill,Corinna D Wong,Alexander H.C.W Agopyan-Miu

doi:10.1038/s41467-019-13396-8

Abstract

Tuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder caused by mutations in TSC1 or TSC2, which encode proteins that negatively regulate mTOR complex 1 (mTORC1). TSC is associated with significant cognitive, psychiatric, and behavioral problems, collectively termed TSC-Associated Neuropsychiatric Disorders (TAND), and the cell types responsible for these manifestations are largely unknown. Here we use cell type-specific Tsc1 deletion to test whether dopamine neurons, which modulate cognitive, motivational, and affective behaviors, are involved in TAND. We show that loss of Tsc1 and constitutive activation of mTORC1 in dopamine neurons causes somatodendritic hypertrophy, reduces intrinsic excitability, alters axon terminal structure, and impairs striatal dopamine release. These perturbations lead to a selective deficit in cognitive flexibility, preventable by genetic reduction of the mTOR-binding protein Raptor. Our results establish a critical role for Tsc1-mTORC1 signaling in setting the functional properties of dopamine neurons, and indicate that dopaminergic dysfunction may contribute to cognitive inflexibility in TSC.

Highlights

Tuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder caused by mutations in TSC1 or TSC2, which encode proteins that negatively regulate mechanistic target of rapamycin (mTOR) complex 1
The goal of this study was to test the sufficiency of manipulating mTOR complex 1 (mTORC1) signaling in DA neurons to drive cellular and behavioral phenotypes relevant to TSC-Associated Neuropsychiatric Disorders (TAND)
We conditionally deleted Tsc[122], which results in loss of function of the Tsc1/2 complex, from DA neurons using DATIRESCre mice[23]

Summary

Introduction

Tuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder caused by mutations in TSC1 or TSC2, which encode proteins that negatively regulate mTOR complex 1 (mTORC1). We show that loss of Tsc[1] and constitutive activation of mTORC1 in dopamine neurons causes somatodendritic hypertrophy, reduces intrinsic excitability, alters axon terminal structure, and impairs striatal dopamine release These perturbations lead to a selective deficit in cognitive flexibility, preventable by genetic reduction of the mTOR-binding protein Raptor. We find that DA neurons are sensitive to changes in mTORC1 signaling, as chronic activation of mTORC1 due to Tsc[1] loss profoundly affects their structure and function resulting in significant impairments in striatal DA release. This dopaminergic deficit is associated with reduced cognitive flexibility in the absence of changes to motor or social behaviors. Our findings pinpoint mTORC1 as a critical regulator of midbrain DA neuron output and suggest that cognitive inflexibility in mTORrelated disorders may involve changes in DA signaling

Objectives

Methods

Results

Conclusion