Defects in syntabulin-mediated synaptic cargo transport associate with autism-like synaptic dysfunction and social behavioral traits.
Defects in syntabulin-mediated synaptic cargo transport associate with autism-like synaptic dysfunction and social behavioral traits.
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DOI：
10.1038/s41380-020-0713-9
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发表时间：
2021-05
影响因子：
11
通讯作者：
Sheng ZH
中科院分区：
文献类型：
--
作者：
Xiong GJ;Cheng XT;Sun T;Xie Y;Huang N;Li S;Lin MY;Sheng ZH
突触的形成和维持需要将新合成的突触蛋白从索马长距离传递到远端突触，这就提出了一个基本问题：受损的转运是否与神经发育障碍（如自闭症）有关。我们以前发现，syntabulin作为一个电机适配器连接驱动蛋白-1电机和突触前货物。在这里，我们报告的缺陷，在syntabulin介导的运输，从而减少形成和成熟的突触是核心的突触机制之一，自闭症样突触功能障碍和社会行为异常。合成表蛋白在小鼠脑中的表达在出生后发育的前两周达到峰值，并在脑成熟过程中逐渐下降。来自条件性syntabulin−/−小鼠（stb cKO）的神经元显示突触前货物运输受损，突触密度和活动区减少，突触传递和长期可塑性改变。有趣的是，stb cKO小鼠表现出核心自闭症样特征，包括社会识别和沟通缺陷，刻板行为增加以及空间学习和记忆受损。这些表型建立了一个新的机制之间的联系减少运输的突触货物和受损的维护突触传递和可塑性，有助于自闭症相关的行为异常。这一概念进一步得到了人类错义变体STB-R178 Q的证实，该变体在自闭症患者中发现，并失去了结合驱动蛋白-1马达的适配器能力。表达STB-R178 Q不能挽救stb cKO神经元中减少的突触形成和受损的突触传递和可塑性。总之，我们的研究表明，突触蛋白介导的运输机制的缺陷是突触功能障碍和行为异常的基础，这些与自闭症有相似之处。Xiong等报道，突触前物质的轴突转运改变是自闭症样突触功能障碍和社会行为异常的核心机制之一。
The formation and maintenance of synapses require long-distance delivery of newly synthesized synaptic proteins from the soma to distal synapses, raising the fundamental question of whether impaired transport is associated with neurodevelopmental disorders such as autism. We previously revealed that syntabulin acts as a motor adaptor linking kinesin-1 motor and presynaptic cargos. Here, we report that defects in syntabulin-mediated transport and thus reduced formation and maturation of synapses are one of core synaptic mechanisms underlying autism-like synaptic dysfunction and social behavioral abnormalities. Syntabulin expression in the mouse brain peaks during the first two weeks of postnatal development and progressively declines during brain maturation. Neurons from conditional syntabulin−/− mice (stb cKO) display impaired transport of presynaptic cargos, reduced synapse density and active zones, and altered synaptic transmission and long-term plasticity. Intriguingly, stb cKO mice exhibit core autism-like traits, including defective social recognition and communication, increased stereotypic behavior, and impaired spatial learning and memory. These phenotypes establish a new mechanistic link between reduced transport of synaptic cargos and impaired maintenance of synaptic transmission and plasticity, contributing to autism-associated behavioral abnormalities. This notion is further confirmed by the human missense variant STB-R178Q, which is found in an autism patient and loses its adaptor capacity for binding kinesin-1 motors. Expressing STB-R178Q fails to rescue reduced synapse formation and impaired synaptic transmission and plasticity in stb cKO neurons. Altogether, our study suggests that defects in syntabulin-mediated transport mechanisms underlie the synaptic dysfunction and behavioral abnormalities that bear similarities to autism. Xiong et al report that altered axonal transport of presynaptic cargos is one of the core mechanisms underlying autism-like synaptic dysfunction and social behavioral abnormalities.
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影响因子：
4.6
作者：
Chen CH;Chen HI;Chien WH;Li LH;Wu YY;Chiu YN;Tsai WC;Gau SS
通讯作者：
Gau SS
征素介导的线粒体沿神经元过程的顺行转运。
影响因子：
7.8
作者：
Cai, Qian;Gerwin, Claudia;Sheng, Zu-Hang
通讯作者：
Sheng, Zu-Hang
影响因子：
3.7
作者：
Gundelfinger ED;Reissner C;Garner CC
通讯作者：
Garner CC
DOI：
10.1016/s0091-6773(73)80166-x
发表时间：
1973-01-01
期刊：
BEHAVIORAL BIOLOGY
影响因子：
--
作者：
DEVOR, M;MURPHY, MR
通讯作者：
MURPHY, MR
影响因子：
2.5
作者：
Hagler, DJ;Goda, Y
通讯作者：
Goda, Y