Mammalian target of rapamycin (mTOR) signaling plays essential roles in brain development. Hyperactive mTOR is an essential pathological mechanism in autism spectrum disorder (ASD). Here, we show that tripartite motif protein 32 (TRIM32), as a maintainer of mTOR activity through promoting the proteasomal degradation of G protein signaling protein 10 (RGS10), regulates the proliferation of medial/lateral ganglionic eminence (M/LGE) progenitors. Deficiency of TRIM32 results in an impaired generation of GABAergic interneurons and autism-like behaviors in mice, concomitant with an elevated autophagy, which can be rescued by treatment embryonically with 3BDO, an mTOR activator. Transplantation of M/LGE progenitors or treatment postnatally with clonazepam, an agonist of the GABAA receptor, rescues the hyperexcitability and the autistic behaviors of TRIM32-/- mice, indicating a causal contribution of GABAergic disinhibition. Thus, the present study suggests a novel mechanism for ASD etiology in that TRIM32 deficiency-caused hypoactive mTOR, which is linked to an elevated autophagy, leads to autism-like behaviors via impairing generation of GABAergic interneurons. TRIM32-/- mouse is a novel autism model mouse.

中文翻译：

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缺乏 TRIM32 通过抑制 mTOR 信号传导导致小鼠 GABA 能中间神经元生成减少和自闭症样行为。

哺乳动物雷帕霉素靶蛋白 (mTOR) 信号传导在大脑发育中起着至关重要的作用。多动 mTOR 是自闭症谱系障碍 (ASD) 的重要病理机制。在这里，我们展示了三方基序蛋白 32 (TRIM32) 作为 mTOR 活性的维持者，通过促进 G 蛋白信号蛋白 10 (RGS10) 的蛋白酶体降解，调节内侧/外侧神经节隆起 (M/LGE) 祖细胞的增殖。TRIM32 的缺乏导致小鼠 GABA 能中间神经元的生成受损和自闭症样行为，伴随着自噬升高，这可以通过用 3BDO（一种 mTOR 激活剂）进行胚胎治疗来挽救。移植 M/LGE 祖细胞或在出生后用氯硝西泮（一种 GABAA 受体激动剂）进行治疗，拯救了 TRIM32-/- 小鼠的过度兴奋和自闭症行为，表明 GABA 能去抑制的因果贡献。因此，本研究提出了 ASD 病因学的一种新机制，即 TRIM32 缺乏引起的 mTOR 活动减退，与自噬升高有关，通过损害 GABA 能中间神经元的生成导致自闭症样行为。TRIM32-/- 小鼠是一种新型的自闭症模型小鼠。