Department of Psychiatry, University of California San Francisco, San Francisco, CA 94158, USA.
Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA 94158, USA.
Cells. 2023 Dec 26;13(1):52. doi: 10.3390/cells13010052.
The mammalian target of rapamycin (mTOR) signaling pathway is a powerful regulator of cell proliferation, growth, synapse maintenance and cell fate. While intensely studied for its role in cancer, the role of mTOR signaling is just beginning to be uncovered in specific cell types that are implicated in neurodevelopmental disorders. Previously, loss of the gene, which results in hyperactive mTOR, was shown to affect the function and molecular properties of GABAergic cortical interneurons (CINs) derived from the medial ganglionic eminence. To assess if other important classes of CINs could be impacted by mTOR dysfunction, we deleted in a caudal ganglionic eminence-derived interneuron group, the vasoactive intestinal peptide (VIP)+ subtype, whose activity disinhibits local circuits. mutant VIP+ CINs reduced their pattern of apoptosis from postnatal days 15-20, resulting in increased VIP+ CINs. The mutant CINs exhibited synaptic and electrophysiological properties that could contribute to the high rate of seizure activity in humans that harbor mutations.
哺乳动物雷帕霉素靶蛋白（mTOR）信号通路是细胞增殖、生长、突触维持和细胞命运的强大调节剂。虽然其在癌症中的作用已被深入研究，但 mTOR 信号通路在神经发育障碍中涉及的特定细胞类型中的作用才刚刚开始被揭示。此前，基因缺失导致 mTOR 过度活跃，这被证明会影响源自内侧神经节隆起的 GABA 能皮质中间神经元（CIN）的功能和分子特性。为了评估 mTOR 功能障碍是否会影响其他重要类型的 CIN，我们在源自尾状神经节隆起的中间神经元群中删除了 ，该群是血管活性肠肽（VIP）+亚型，其活性可抑制局部回路。 突变的 VIP+CIN 减少了其从出生后第 15-20 天的凋亡模式，导致 VIP+CIN 增加。突变的 CIN 表现出的突触和电生理特性可能导致携带 突变的人类癫痫活动率升高。
