Cerebellar Topography in Autism and Rescue of Autism-Related Behaviors in Autism Mouse Models

Background:

Autism Spectrum Disorders (ASDs) are prevalent neurodevelopmental disorders marked by social impairments, repetitive behaviors, and cognitive inflexibility. Despite a prevalence exceeding 1%, underlyingmechanisms are poorly understood while targeted therapies and their guiding parameters are needed. Recent evidence has implicated the cerebellum in ASD pathogenesis, and we have recently demonstrated that cerebellar dysfunction is sufficient to generate autism-relevant behaviors in mice. However, the cerebellar topography regulating autism-related behaviors and the neural circuits regulating those behaviors remain poorly understood.

Objectives: to identify cerebellar topography and cerebellar-regulated circuits underlying autism-related behaviors

Methods: To achieve these objectives, we have combined genetic mouse models, MR imaging, and targeted, in vivo chemogenetic- mediated neuromodulation paired with in vivo electrophysiology and detailed behavioral analyses.

Results: Using these methods, we have identified the clinically implicated cerebellar sub-region, Right Crus I, as a critical region in the regulation of autism-related behaviors. We determine that inhibition of this domain is sufficient to generate social, repetitive, and inflexible behaviors in mice. Moreover, we demonstrate that stimulation of this sub-region is sufficient to rescue social deficits in an ASD mouse model even during adulthood. We then identified functional connectivity between right Crus I and cortical association areas, connectivity that is disrupted in this ASD mouse model and in children with ASD. Modulation of these cortical areas in turn mediates cerebellar-regulated ASD behaviors.

Conclusions: These findings, thus, not only further our mechanistic understanding of the cerebellar contribution to ASD but also offer novel therapeutic targets and strategies for the treatment of autism-related behaviors.