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CADM1, a molecule linked to Autism Spectrum Disorder, forms a synaptic complex and its function.

CADM1 是一种与自闭症谱系障碍相关的分子，它形成突触复合体及其功能。

基本信息

批准号：
21500334
负责人：
MOMOI Takashi
金额：
$ 2.91万
依托单位：
International University of Health and Welfare
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2009
资助国家：
日本
起止时间：
2009 至 2011
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21500334/
关键词：
シナプス Cadm1 自閉症

项目摘要

Autism spectrum disorder (ASD), a neurodevelopmental disorder of uncertain molecular origin, has been previously linked to mutations in synaptic adhesion molecules, animbalance of excitatory and inhibitory synapses, and/or an impaired cerebellum. Mutations in the synaptic adhesion protein CADM1 (RA175/SynCAM1) are associated with ASD, and Cadm1 knock out (KO) mice exhibit smaller cerebella with decreased number of synapse of Purkinje cells and some ASD-like symptoms, including impaired ultrasonic vocalization. In the present study, we examined the alteration of the Cadm1 synaptic complex in the mouse cerebellum at postnatal stages. The C-terminal peptide of Cadm1 associated with Mupp1 at PDZ(1-5), a scaffold protein containing 13 PDZ domains, which interacted with GABBR2 at PDZ13, but not with PSD-95. Cadm1 co-localized with Mupp1 and GABBR2 on the dendrites of hippocampal neurons cultured in vitro and in the molecular layers of the cerebellum. These observations suggest that the Cadm1 synaptic receptor complex,including Mupp1-GABBR2, is located on the dendrites of Purkinje cells. The amount of GABBR2 protein but not mRNA was increased in the cerebella of Cadm1 KO mice, suggesting that lack of Cadm1 does not affect transcription but may stabilize the Mupp1-GABBR2 receptor complex. Up-regulation of GABBR2 in the cerebellum in the absence of CADM1 may be associated with ASD pathogenesis.

自闭症谱系障碍（ASD）是一种分子起源不确定的神经发育障碍，以前与突触粘附分子突变、兴奋性和抑制性突触失衡和/或小脑受损有关。突触粘附蛋白CADM1 （RA175/SynCAM1）的突变与ASD有关，CADM1敲除（KO）小鼠表现出小脑变小、浦肯野细胞突触数量减少和一些ASD样症状，包括超声发声受损。在本研究中，我们检测了小鼠出生后小脑中Cadm1突触复合体的变化。Cadm1的c端肽在PDZ位点与Mupp1结合（1-5），这是一种含有13个PDZ结构域的支架蛋白，它在PDZ13位点与GABBR2相互作用，但不与PSD-95相互作用。Cadm1与Mupp1和GABBR2共定位于体外培养海马神经元树突和小脑分子层。这些观察结果表明，Cadm1突触受体复合物，包括Mupp1-GABBR2，位于浦肯野细胞的树突上。Cadm1 KO小鼠小脑中GABBR2蛋白而非mRNA的数量增加，表明Cadm1的缺乏不影响转录，但可能稳定Mupp1-GABBR2受体复合物。在CADM1缺失的情况下，小脑GABBR2的上调可能与ASD的发病机制有关。