Polina Kosillo - Cell-autonomous gatekeeping of dopaminergic neurotransmission by mTOR pathway

The Future of Dopamine - ViDA Symposium - Nov 19, 2020

Polina Kosillo
Bateup Lab, University of California, Berkeley

Cell-autonomous gatekeeping of dopaminergic neurotransmission by mTOR pathway

The neurodevelopmental disorder Tuberous Sclerosis Complex (TSC) is caused by loss-of-function mutations in the TSC1/TSC2 genes which lead to constitutive mTORC1 activation. TSC patients present with significantly elevated rates of dopamine (DA)-related neuropsychiatric conditions, and we hypothesized DA neuron involvement. To test this, I generated mice with conditional Tsc1 deletion selectively in DA neurons (DA-Tsc1 KO) and found that mTORC1 hyperactivity caused profound structural and functional changes. DA-Tsc1 KO neurons had pronounced somato-dendritic and axonal hypertrophy, reduced intrinsic excitability, and a significant impairment in evoked striatal DA release, despite increased DA production. These structural and functional changes were sufficient to induce a selective deficit in cognitive flexibility: DA-Tsc1 KO mice took considerably longer to update their behavioral strategy in a reversal learning task, showing perseveration, commonly reported across neuropsychiatric conditions. I further established that genetic reduction of Raptor, an obligatory protein component of mTORC1, in DA-Tsc1 KO mice reduced mTORC1 hyperactivation and prevented both DA release and cognitive flexibility deficits. In a follow up study, I address whether two arms of mTOR pathway are equivalent in their governance of the DA system. mTORC1 and mTORC2 have distinct functional roles, and suppression of either complex is possible via genetic reduction of the obligatory binding partners, Raptor and Rictor, respectively. I showed that mTORC1 suppression is severely detrimental to DA neurons causing somato-dendritic hypotrophy and corresponding intrinsic hyperexcitability, together with profound reduction in DA synthesis and release. In contrast, mTORC2 suppression has minimal impact on DA neurons. Across the two studies, my work establishes that DA neurons are exquisitely sensitive to mTORC1 signaling which serves as a cell-autonomous gatekeeper of dopaminergic neurotransmission.