Autism Spectrum Disorder: The Cerebellum, Genes, and Pathways

Autism spectrum disorder (ASD) is a complex, heterogenous, and prevalent neurodevelopmental disorder characterized by core symptoms, including social communication deficits, restrictive interests, and repetitive behaviors. Although environmental factors contribute to the etiology of ASD, the disorder has a strong genetic basis, although the specific genes involved in causing or contributing to the disorder remain to be conclusively identified. Whereas previous studies have focused on the cerebral cortex, hippocampus, and associated brain regions to uncover the underpinnings of ASD, emerging evidence indicates that dysfunction of the cerebellum is one of the most consistent associates of ASD. Traditionally thought to function solely in motor control, more recent studies have established that projections from the cerebellum make mono- and polysynaptic connections to a variety of non-motor areas including the cerebral cortex, hypothalamus, and hippocampus, and is involved in a range of cognitive, sensory, and behavioral functions. While several reviews of the molecular underpinnings of ASD have focused on the other brain regions, primarily the cortex, in this review we describe the key role that the cerebellum plays in the development of ASD and then focus on genetic variations that cause ASD, focusing on genes expressed and studied in the cerebellum. We have divided the ASD-associated genes in two subgroups-those that have been identified through a candidate gene approach with knowledge of their function in the cerebellum and their relationship to ASD subsequently confirmed in experimental models, and those identified through unbiased genetic analyses of individuals with ASD, many of which have not yet been characterized extensively and/or not studied in animal models. We also provide recently reported information on non-genetic factors that combine with genetic factors to promote ASD. Together, we hope our review will provide information on recent and significant findings related to the cerebellar underpinnings in ASD.