Dopamine neuron morphology and output are differentially controlled by mTORC1 and mTORC2.
Dopamine neuron morphology and output are differentially controlled by mTORC1 and mTORC2.
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多巴胺神经元的形态和输出是由mTORC 1和mTORC 2差异控制的。
DOI：
10.7554/elife.75398
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发表时间：
2022-07-26
期刊：
影响因子：
7.7
通讯作者：
Bateup, Helen S.
中科院分区：
文献类型：
--
作者：
Kosillo, Polina;Ahmed, Kamran M.;Aisenberg, Erin E.;Karalis, Vasiliki;Roberts, Bradley M.;Cragg, Stephanie J.;Bateup, Helen S.
mTOR通路是细胞生长和代谢的重要调节因子。中脑多巴胺神经元对mTOR信号传导状态特别敏感，因为mTOR的激活或抑制改变了它们的形态和生理学。mTOR存在于两种不同的多蛋白复合物中，称为mTORC 1和mTORC 2。这些复合物如何影响多巴胺神经元的特性，以及它们是否具有相似或不同的功能尚不清楚。在这里，我们研究了多巴胺神经元特异性缺失的Rptor或Rictor，分别编码mTORC 1或mTORC 2的强制性组件的小鼠。我们发现，抑制mTORC1强烈和广泛影响多巴胺神经元的结构和功能，导致体树突和轴突萎缩，增加内在兴奋性，减少多巴胺的产生，并损害多巴胺的释放。相比之下，mTORC2的抑制具有更微妙的效果，选择性改变腹侧被盖区多巴胺神经元的输出。两种mTOR复合物的破坏导致多巴胺释放的明显缺陷，证明了平衡mTORC1和mTORC2信号传导对多巴胺能功能的重要性。
The mTOR pathway is an essential regulator of cell growth and metabolism. Midbrain dopamine neurons are particularly sensitive to mTOR signaling status as activation or inhibition of mTOR alters their morphology and physiology. mTOR exists in two distinct multiprotein complexes termed mTORC1 and mTORC2. How each of these complexes affect dopamine neuron properties, and whether they have similar or distinct functions is unknown. Here, we investigated this in mice with dopamine neuron-specific deletion of Rptor or Rictor, which encode obligatory components of mTORC1 or mTORC2, respectively. We find that inhibition of mTORC1 strongly and broadly impacts dopamine neuron structure and function causing somatodendritic and axonal hypotrophy, increased intrinsic excitability, decreased dopamine production, and impaired dopamine release. In contrast, inhibition of mTORC2 has more subtle effects, with selective alterations to the output of ventral tegmental area dopamine neurons. Disruption of both mTOR complexes leads to pronounced deficits in dopamine release demonstrating the importance of balanced mTORC1 and mTORC2 signaling for dopaminergic function.