A complex of synaptic adhesion molecule CADM1, a molecule related to autism spectrum disorder, with MUPP1 in the cerebellum

Abstract

Mutations in the synaptic adhesion protein CADM1 (RA175/SynCAM1) are associated with autism spectrum disorder (ASD), a neurodevelopmental disorder of uncertain molecular origin. 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 this study, we examined the alteration of the Cadm1 synaptic complex in the mouse cerebellum at post-natal stages. The C-terminal peptide of Cadm1 associated with Mupp1 at PSD-95/Dlg/ZO-1 (PDZ)(1-5), a scaffold protein containing 13 PDZ domains, which interacted with gamma-aminobutyric acid type B receptor (GABBR)2 at PDZ13, but not with PSD-95. The GABBR2 was detected in a set of proteins interacting with Cadm1 C-terminal. Cadm1 colocalized with Mupp1 and GABBR2 on the dendrites of Purkinje cells in the molecular layers of the developing cerebellum and on the dendrites of hippocampal neurons cultured in vitro. 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 of GABBR2, but may stabilize the Mupp1-GABBR2 complex; the Mupp1-GABBR2 interaction may be stabilized by conformational change in Mupp1 or association with other adhesion molecules and by anchorage to the post-synaptic membrane. Up-regulation of GABBR2 in the cerebellum in the absence of CADM1 may be associated with ASD pathogenesis.