Csmd2 is a Synaptic Transmembrane Protein that Interacts with PSD-95

Abstract

Mutations and copy number variants of the Cub and Sushi Multiple Domains 2 (CSMD2) gene are associated with schizophrenia and autism spectrum disorder. CSMD2 is a single-pass transmembrane protein with a large extracellular domain comprising repeats of Cub and Sushi domains. Although the biological functions of CSMD2 have not been studied, the association between CSMD2 variants and cognitive function suggest that it may have a role in brain development or function. In this study, we show that mouse Csmd2 is expressed in excitatory and inhibitory neurons in the brain. Csmd2 protein exhibits a somatodendritic localization in the neocortex and hippocampus, with smaller puncta localizing further out in the neuropil. We show that many of these Csmd2 puncta co-localize with the synaptic protein PSD-95. Using immunohistochemical and biochemical methods, we further demonstrate that Csmd2 localizes to dendritic spines and is enriched in the postsynaptic density. We also find Csmd2 at ribbon synapses of the inner plexiform layer of the retina, suggesting a broader synaptic function of Csmd2 in the central nervous system. Finally, we show that the cytoplasmic tail domain of Csmd2 interacts with synaptic scaffolding proteins of the membrane-associated guanylate kinase (MAGUK) family. The association between Csmd2 and MAGUK member PSD-95 is dependent on a PDZ-binding domain on the Csmd2 tail, which is also required for synaptic targeting of Csmd2. Together, these results point toward a function for Csmd2 in dendrites and synapses, which may account for its association with several psychiatric disorders.