Tsc1-mTORC1 signaling controls striatal dopamine release and cognitive flexibility

Polina Kosillo, Natalie M. Doig, Kamran M. Ahmed, Alexander H.C.W. Agopyan-Miu, Corinna D. Wong, Lisa Conyers, Sarah Threlfell, Peter J. Magill and Helen S. Bateup ()
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Polina Kosillo: University of California, Berkeley
Natalie M. Doig: University of Oxford
Kamran M. Ahmed: University of California, Berkeley
Alexander H.C.W. Agopyan-Miu: University of California, Berkeley
Corinna D. Wong: University of California, Berkeley
Lisa Conyers: University of Oxford
Sarah Threlfell: University of Oxford
Peter J. Magill: University of Oxford
Helen S. Bateup: University of California, Berkeley

Nature Communications, 2019, vol. 10, issue 1, 1-19

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-13396-8

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