Autism-like Deficits in Shank3-Deficient Mice Are Rescued by Targeting Actin Regulators.
Autism-like Deficits in Shank3-Deficient Mice Are Rescued by Targeting Actin Regulators.
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DOI：
10.1016/j.celrep.2015.04.064
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发表时间：
2015-06-09
期刊：
影响因子：
8.8
通讯作者：
Yan Z
中科院分区：
文献类型：
--
作者：
Duffney LJ;Zhong P;Wei J;Matas E;Cheng J;Qin L;Ma K;Dietz DM;Kajiwara Y;Buxbaum JD;Yan Z
Shank 3基因的单倍不足是自闭症的一个高度流行和渗透的危险因素，Shank 3基因编码一种在神经元突触处的支架蛋白。通过结合行为学、电生理学、生物化学、影像学和分子生物学方法，我们发现Shank 3缺陷小鼠表现出自闭症样的社会缺陷和重复行为，以及前额叶皮层NMDAR突触功能和突触分布的显著减少。与此同时，Shank 3缺陷小鼠有一个显着的损失皮质肌动蛋白丝，这是与减少Rac 1/PAK活性和增加的活性cofilin，主要的肌动蛋白解聚因子。在Shank 3缺陷型小鼠中，通过抑制cofilin或激活Rac 1来挽救社交缺陷和NMDAR功能减退，并且在野生型小鼠中通过抑制PAK或Rac 1来诱导。这些结果表明，突触肌动蛋白丝的异常调节和突触NMDAR的丢失有助于自闭症样表型的表现。因此，靶向肌动蛋白调节剂为自闭症治疗提供了一种新的策略。
Haploinsufficiency of the Shank3 gene, which encodes a scaffolding protein at glutamatergic synapses, is a highly prevalent and penetrant risk factor for autism. Using combined behavioral, electrophysiological, biochemical, imaging and molecular approaches, we find that Shank3-deficient mice exhibit autism-like social deficits and repetitive behaviors, as well as the significantly diminished NMDAR synaptic function and synaptic distribution in prefrontal cortex. Concomitantly, Shank3-deficient mice have a marked loss of cortical actin filaments, which is associated with the reduced Rac1/PAK activity and increased activity of cofilin, the major actin depolymerizing factor. The social deficits and NMDAR hypofunction are rescued by inhibiting cofilin or activating Rac1 in Shank3-deficient mice, and are induced by inhibiting PAK or Rac1 in wild-type mice. These results indicate that the aberrant regulation of synaptic actin filaments and loss of synaptic NMDARs contribute to the manifestation of autism-like phenotypes. Thus, targeting actin regulators provides a novel strategy for autism treatment.
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影响因子：
30.8
作者：
Durand, Christelle M.;Betancur, Catalina;Bourgeron, Thomas
通讯作者：
Bourgeron, Thomas
影响因子：
6.2
作者：
Bozdagi O;Sakurai T;Papapetrou D;Wang X;Dickstein DL;Takahashi N;Kajiwara Y;Yang M;Katz AM;Scattoni ML;Harris MJ;Saxena R;Silverman JL;Crawley JN;Zhou Q;Hof PR;Buxbaum JD
通讯作者：
Buxbaum JD
影响因子：
16.2
作者：
Frost, Nicholas A.;Shroff, Hari;Kong, Huihui;Betzig, Eric;Blanpied, Thomas A.
通讯作者：
Blanpied, Thomas A.
影响因子：
11
作者：
Durand CM;Perroy J;Loll F;Perrais D;Fagni L;Bourgeron T;Montcouquiol M;Sans N
通讯作者：
Sans N
影响因子：
6.2
作者：
Betancur C;Buxbaum JD
通讯作者：
Buxbaum JD