Abstract
The cerebellum has been repeatedly implicated in gene expression, rodent model and post-mortem studies of autism spectrum disorder (ASD). How cellular and molecular anomalies of the cerebellum relate to clinical manifestations of ASD remains unclear. Separate circuits of the cerebellum control different sensorimotor behaviors, such as maintaining balance, walking, making eye movements, reaching, and grasping. Each of these behaviors has been found to be impaired in ASD, suggesting that multiple distinct circuits of the cerebellum may be involved in the pathogenesis of patients' sensorimotor impairments. We will review evidence that the development of these circuits is disrupted in individuals with ASD and that their study may help elucidate the pathophysiology of sensorimotor deficits and core symptoms of the disorder. Preclinical studies of monogenetic conditions associated with ASD also have identified selective defects of the cerebellum and documented behavioral rescues when the cerebellum is targeted. Based on these findings, we propose that cerebellar circuits may prove to be promising targets for therapeutic development aimed at rescuing sensorimotor and other clinical symptoms of different forms of ASD.
Highlights
Converging clinical and preclinical data identify an important role for the cerebellum in the pathogenesis of both monogenic syndromes associated with ASD and idiopathic ASD
The cerebellum’s rapid postnatal growth suggests that there may be critical periods of development during which it helps to scaffold the specialization of association cortices and other later developing brain systems (Rice and Barone, 2000)
While gene expression studies show that ASD implicated networks are highly expressed in postnatal cerebellum, the timing of cerebellar defects across circuits has not yet been assessed
Summary
The majority of in vivo brain studies of individuals with autism spectrum disorder (ASD) have focused on neural networks involved in social behavior, language, and behavioral and cognitive flexibility—the defining features of the disorder (American Psychiatric Association, 2013). There are multiple factors that have limited progress toward identifying brain mechanisms in ASD including the complexity of the psychological/behavioral constructs that have been most systematically investigated (e.g., theory of mind processing), limited knowledge about their neural underpinnings, clinical, and neurobiological heterogeneity across the autism spectrum, a lack of integration of knowledge about the developmental neurobiology of relevant brain systems, and failures to link in vivo case-control studies of psychological dimensions with what is known about histopathological and molecular mechanisms associated with ASD
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