Abnormal cerebellar development is involved in dystonia-like behaviors and motor dysfunction of autistic BTBR mice

Abstract Background: Motor control and learning impairments are common complications in autistic individuals. Abnormal cerebellar development during critical phases may disrupt these motor functions and lead to the development of autistic motor dysfunction. However, the underlying mechanisms behind these impairments are not clear.Methods: Dystonic behavior was elicited using tail suspension. Motor control and learning were detected by means of the grid hang test, ladder rung walking, accelerating rotarod, and open field locomotion. Cerebellar development was morphometrically and histologically detected during critical phases. RNA sequencing was used to compare differential gene expression to provide an in-depth interpretation of molecular mechanisms.Results: BTBR mice, as a model of autism, exhibited severe dystonic behavior and motor coordination or motor learning impairments. The onset of these abnormal movements coincided with the increased proliferation of granule neurons and enhanced foliation, and Purkinje cells exhibited morphological hypotrophy with increased dendritic spine formation but suppressed maturation. The migration of granule neurons seemed unaffected. Transcriptional analyses confirmed the differential expression of genes involved in abnormal neurogenesis and revealed TRPC6 as a critical regulator in proliferation and synaptic formation. Conclusion: These findings indicate that abnormal cerebellar development is closely related to dystonia and motor dysfunction of BTBR mice and that TRPC6 may be a novel risk gene for ASD that may participate in the pathological process of autistic movement disorders.