Dissection of Cerebellar-Cerebro Cortical Circuits in ASD Reveals Therapeutic Opportunities for Circuit Modulation
Autism Spectrum Disorders (ASDs) are prevalent neurodevelopmental disorders marked by social impairments, repetitive behaviors, and cognitive inflexibility. Despite a prevalence exceeding 1%, underlying mechanisms are poorly understood while targeted therapies and their guiding parameters are needed. Recent evidence has implicated the cerebellum in ASD pathogenesis, and we have demonstrated that cerebellar dysfunction is sufficient to generate autism-relevant behaviors (social dysfunction, repetitive/inflexible behaviors) in a genetic mouse model and via chemogenetic disruption of function in a specific cerebellar domain, CrusI.
Objectives: However, how the cerebellum regulates autism-related behaviors and the neural circuit networks regulated by the cerebellum, and in particular CrusI, are not well understood.
Methods: In this study, using targeted, in vivo chemogenetic and optogenetic neural circuit modulation combined with in vivo electrophysiology, anatomic mapping (using a host of viral tracing techniques), and behavioral evaluation, we sought to identify cerebellar-regulated circuits that regulate autism-relevant behaviors.
Results: Using these above methods, we have delineated specific cerebro-cortical circuits implicated in ASD that are regulated by cerebellar circuits. We show the anatomic basis for these cerebello-cerebrocortical circuits - from CrusI to cerebellar output nucleus to thalamus to cortical association areas - and demonstrate functional consequences of disruption of each circuit component on ASD-related behaviors while also demonstrating that modulation of these specific circuits can ameliorate ASD behaviors in a genetic ASD mouse model.
Conclusions: These findings delineate the anatomic basis for cerebellar - cerebro-cortical connectivity and demonstrate functional impact of these circuits on ASD-related behaviors. These studies, thus, further our mechanistic understanding of the neural circuit contribution to ASD while also further demonstrating important roles for cerebellar-cerebro cortical circuits in the regulation of ASD behaviors. In addition, these studies raise the possibility that neural circuit modulation may offer potential, novel therapeutic targets for the treatment of autism-related behaviors.