Autism spectrum disorder: The cerebellum, genes, and pathways

Autism spectrum disorders (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. Previous studies have focused on the cerebral cortex, hippocampus, and associated brain regions to uncover the underpinnings of ASD. However, dysfunction of the cerebellum has emerged as one of the most consistent associates of ASD. Although 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 cerebral cortex, hypothalamus, hippocampus, and is involved in a range of cognitive, sensory, and behavioral functions. Whereas the cellular and molecular mechanisms underlying ASD are far from understood, information gained from genetic studies in humans and animal models of ASD have identified a large number of genes and several signaling pathways the dysfunction of which may contribute to the disorder. In this review, we summarize recent evidence on the key role that the cerebellum plays in the development of ASD and then focus on genetic variations that cause ASD, focusing, to the extent possible, on the cerebellum. We have divided the ASD-associated gene 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.