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

自闭症谱系障碍(ASD)是一种分子来源不明的神经发育障碍，先前已被认为与突触黏附分子突变、兴奋性突触和抑制性突触的动态平衡和/或小脑受损有关。突触黏附蛋白CADM1(RA175/SynCAM1)的突变与ASD有关，CAdm1基因敲除(KO)小鼠的小脑较小，浦肯野细胞突触数量减少，以及一些ASD样症状，包括超声波发声障碍。在本研究中，我们研究了出生后小鼠小脑中CAdm1突触复合体的变化。CAdm1的C端肽与PDZ(1-5)的Mupp1结合，这是一个含有13个PDZ结构域的支架蛋白，它与PDZ13的GABBR2相互作用，但不与PSD-95相互作用。CAdm1与Mupp1和GABBR2共同定位于体外培养的海马神经元的树突和小脑的分子层。这些观察结果表明，包括Mupp1-GABBR2在内的CAdm1突触受体复合体位于浦肯野细胞的树突上。CAdm1KO小鼠小脑中GABBR2蛋白的含量增加，但不增加mRNA量，提示CAdm1的缺失不影响转录，但可能稳定Mupp1-GABBR2受体复合体。CADM1缺失时，小脑GABBR2表达上调可能与ASD的发病有关。

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.