Deficiency Leads to Motor Impairments and Autism-Like Behaviors via Dysfunction of Cerebellar Purkinje Cells in Mice.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with highly heritable heterogeneity. Mutations of CUB and sushi multiple domains 3 () gene have been reported in individuals with ASD. However, the underlying mechanisms of CSMD3 for the onset of ASD remain unexplored. Here, using male knock-out ( ) mice, we found that genetic deletion of produced core autistic-like symptoms (social interaction deficits, restricted interests, and repetitive and stereotyped behaviors) and motor dysfunction in mice, indicating that the gene can be considered as a candidate for ASD. Moreover, we discovered that the ablation of in mice led to abnormal cerebellar Purkinje cell (PC) morphology in Crus I/II lobules, including aberrant developmental dendritogenesis and spinogenesis of PCs. Furthermore, combining fiber photometry calcium imaging and electrophysiological recordings, we showed that the mice exhibited an increased neuronal activity (calcium fluorescence signals) in PCs of Crus I/II lobules in response to movement activity, as well as an enhanced intrinsic excitability of PCs and an increase of excitatory rather than inhibitory synaptic input to the PCs, and an impaired long-term depression at the parallel fiber-PC synapse. These results suggest that CSMD3 plays an important role in the development of cerebellar PCs. Loss of CSMD3 causes abnormal PC morphology and dysfunction in the cerebellum, which may underlie the pathogenesis of motor deficits and core autistic-like symptoms in mice. Our findings provide novel insight into the pathophysiological mechanisms by which mutations cause impairments in cerebellar function that may contribute to ASD. Autism spectrum disorder (ASD) is a neurodevelopmental disorder with highly heritable heterogeneity. Advances in genomic analysis have contributed to numerous candidate genes for the risk of ASD. Recently, a novel giant gene encoding a protein with CUB and sushi multiple domains (CSMDs) has been identified as a candidate gene for ASD. However, the underlying mechanisms of for the onset of ASD remain largely unknown. Here, we unravel that loss of results in abnormal morphology, increased intrinsic excitabilities, and impaired synaptic plasticity in cerebellar PCs, subsequently leading to motor deficits and ASD-like behaviors in mice. These results provide novel insight into the pathophysiological mechanisms by which mutations cause impairments in cerebellar function that may contribute to ASD.