Cerebellar Influence on the Development of Flexible Behavior and Its Neocortical Substrates

Abstract

The cerebellum is the most frequently observed site of structural abnormality in individuals with autism spectrum disorder (ASD), but its role in the etiology of ASD is unknown. We hypothesized that the cerebellum guides the maturation of distal neocortical regions during sensitive periods of development. The developmental diaschisis hypothesis predicts that cerebellar disruptions can impair the refinement of neocortical circuits, leading to ASD-related pathologies. Using the Purkinje cell-specific L7-tuberous sclerosis 1 (Tsc1) heterozygous mice as a model of pan-cerebellar perturbation, we found increased spine density on apical and basal dendrites of layer II/III pyramidal neurons in the medial prefrontal cortex (mPFC). Previous work on the Tsc1 model demonstrated that heterozygous Tsc1 mice display ASD-like behavioral deficits including social impairment and repetitive behavior. We explored whether region-specific cerebellar perturbations also alter social behavior and spine plasticity in functionally correlated neocortical regions. Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) were expressed in cerebellar lobule VI or crus I via region-specific injections of AAV8-hSyn-hM4D(Gi)-mCherry to inhibit activity of molecular layer interneurons throughout development (postnatal day 21-60). In the three-chamber sociability assay, mice with DREADDs expressed in lobule VI displayed significantly decreased social preference compared to controls injected with saline. We found no significant difference in spine density and morphology of layer II/III pyramidal neurons in the mPFC or in layer II/III and V pyramidal neurons in the anterior cingulate cortex between the DREADDs and saline-control groups. This study provides experimental evidence and suggests possible synaptic mechanisms for the role of the cerebellum in the development of flexible and social behavior and in the maturation of neocortical circuits.