THE SYNAPTIC ROLE OF CADHERIN-13, A PROTEIN ASSOCIATED WITH AUTISM SPECTRUM DISORDERS (ASD)

Recent advances in human genetics have enabled the identification of specific risk genes associated with behavioral disorders such as autism spectrum disorders (ASD). Among them, there is a significant number of genes encoding synaptic proteins, such as the adhesion molecule Cadherin-13 (CDH13). CDH13 is expressed in various regions of the brain, including the cerebellum, which is known to be implicated in ASD symptomatology. Our previous works have demonstrated that the protein localizes to the axonal terminals of Golgi cells in the granular layer of the cerebellum, and contribute to the development of a specific inhibitory synapse known as the glomerulus. However, the precise molecular and cellular mechanisms implicating CDH13 in cerebellar synaptogenesis remain unclear. To address this issue, we first aimed to elucidate the interactions of CDH13 with its synaptic partners. So far, CDH13 Co-IP followed by mass spectrometry analyses on cerebellum samples, have revealed that CDH13 is part of a major synaptogenic protein complex containing NLG2 and IGSF9B although it does not interact with them directly. In parallel, histological staining indicates that CDH13 is expressed specifically across all Golgi cells subpopulations. To investigate its potential synaptic role in Golgi cells we generated a conditional knock-out mouse line. Using the classical three-chambers social interaction test, we found that cKO mice exhibit alterations in social behaviors reminiscent of those observed in ASD mouse models. Overall, our work suggests that CDH13 may contribute to the shaping of cerebellar circuits involved in social behaviors, providing new insight into cerebellar contribution to cognitive functions.