Absence of TRIM32 leads to reduced GABAergic interneuron generation and Autism-like behaviors in mice via suppressing mTOR signaling
Absence of TRIM32 leads to reduced GABAergic interneuron generation and Autism-like behaviors in mice via suppressing mTOR signaling
复制标题
TRIM32 的缺失通过抑制 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
DOI：
10.1093/cercor/bhz306
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发表时间：
2020
期刊：
影响因子：
3.7
通讯作者：
Melitt
中科院分区：
文献类型：
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作者：
Jian-Wei Zhu;Ming-Ming Zou;Yi-Fei Li;Wen-Jin Chen;Ji-Chuan Liu;Hong Chen;Li-Pao Fang;Yan Zhang;Zhao-Tao Wang;Ji-Bo Chen;Wenhui Huang;Shen Li;Wei-Qiang Jia;Qin-Qin Wang;Xue-Chu Zhen;Chun-Feng Liu;Shao Li;Zhi-Cheng Xiao;Guo-Qiang Xu;Jens C Schwamborn;Melitt
哺乳动物雷帕霉素靶蛋白（mTOR）信号转导在脑发育中起着重要作用。过度活跃的mTOR是自闭症谱系障碍（ASD）的重要病理机制。在这里，我们表明，三方基序蛋白32（TRIM 32），作为一个mTOR活性的维护者，通过促进G蛋白信号蛋白10（RGS 10）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。TRIM 32的缺乏导致小鼠中GABA能中间神经元的产生受损和自闭症样行为，伴随着自噬的升高，这可以通过用3BDO（一种mTOR激活剂）进行胚胎治疗来挽救。M/LGE祖细胞移植或出生后用氯硝西泮（一种GABA受体激动剂）治疗，挽救了TRIM 32 −/−小鼠的过度兴奋和自闭症行为，表明GABA能去抑制的因果作用。因此，本研究提出了ASD病因学的新机制，即TRIM 32缺陷引起的低活性mTOR，其与升高的自噬有关，通过损害GABA能中间神经元的产生导致自闭症样行为。TRIM 32 −/−小鼠是一种新型自闭症模型小鼠。
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 GABAAreceptor, 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.