Journal article
Tsc1-mTORC1 signaling controls striatal dopamine release and cognitive flexibility
- 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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, 3.0MB, Terms of use)
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- Publisher copy:
- 10.1038/s41467-019-13396-8
Authors
- Publisher:
- Nature Research
- Journal:
- Nature communications More from this journal
- Volume:
- 10
- Issue:
- 1
- Article number:
- 5426
- Publication date:
- 2019-11-28
- Acceptance date:
- 2019-11-07
- DOI:
- EISSN:
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2041-1723
- ISSN:
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2041-1723
- Pmid:
-
31780742
- Language:
-
English
- Pubs id:
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1077055
- Local pid:
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pubs:1077055
- Deposit date:
-
2020-02-05
Terms of use
- Copyright holder:
- Kosillo et al.
- Copyright date:
- 2019
- Rights statement:
- Copyright © The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
- Licence:
- CC Attribution (CC BY)
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