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

自闭症谱系障碍（ASD）是一种分子起源不确定的神经发育障碍，先前已将其与突触粘附分子的突变、兴奋性和抑制性突触的不平衡和/或小脑受损联系起来。突触粘附蛋白CADM 1（RA 175/SynCAM 1）的突变与ASD相关，并且Cadm 1敲除（KO）小鼠表现出小脑较小，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，我们研究了在出生后阶段的小鼠小脑中的Cadm 1突触复合体的变化。Cadm 1的C端肽与Mupp 1在PDZ（1-5）处结合，PDZ（1-5）是一种含有13个PDZ结构域的支架蛋白，其与GABBR 2在PDZ 13处相互作用，但不与PSD-95相互作用。Cadm 1与Mupp 1和GABBR 2共定位于体外培养的海马神经元树突和小脑的分子层中。这些观察结果表明，Cadm 1突触受体复合物，包括Mupp 1-GABBR 2，位于浦肯野细胞的树突上。Cadm 1基因敲除小鼠小脑中GABBR 2蛋白而非mRNA的量增加，表明Cadm 1的缺乏不影响转录，但可能稳定Mupp 1-GABBR 2受体复合物。在CADM 1缺失的情况下，小脑中GABBR 2的上调可能与ASD发病机制相关。

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.