Tsc1-mTORC1 signaling controls striatal dopamine release and cognitive flexibility.,Nature Communications

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Tsc1-mTORC1 signaling controls striatal dopamine release and cognitive flexibility.
Nature Communications ( IF 14.7 ) Pub Date : 2019-11-28 , DOI: 10.1038/s41467-019-13396-8
Polina Kosillo ₁ , Natalie M Doig ₂ , Kamran M Ahmed ₁ , Alexander H C W Agopyan-Miu ₁ , Corinna D Wong ₁ , Lisa Conyers ₂ , Sarah Threlfell _{3,

4} , Peter J Magill _{2,

4} , Helen S Bateup _{1,

5,

6}

Affiliation

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.

中文翻译：

Tsc1-mTORC1 信号传导控制纹状体多巴胺释放和认知灵活性。

结节性硬化症复合体 (TSC) 是一种由 TSC1 或 TSC2 突变引起的神经发育障碍，TSC1 或 TSC2 编码负调节 mTOR 复合体 1 (mTORC1) 的蛋白质。 TSC 与严重的认知、精神和行为问题相关，统称为 TSC 相关神经精神疾病 (TAND)，而导致这些表现的细胞类型很大程度上未知。在这里，我们使用细胞类型特异性 Tsc1 缺失来测试调节认知、动机和情感行为的多巴胺神经元是否参与 TAND。我们发现，多巴胺神经元中 Tsc1 的缺失和 mTORC1 的组成性激活会导致体树突肥大，降低内在兴奋性，改变轴突末端结构，并损害纹状体多巴胺的释放。这些扰动会导致认知灵活性的选择性缺陷，这可以通过 mTOR 结合蛋白 Raptor 的基因减少来预防。我们的结果确立了 Tsc1-mTORC1 信号在设定多巴胺神经元功能特性中的关键作用，并表明多巴胺能功能障碍可能导致 TSC 认知不灵活。

更新日期：2019-11-29

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