Motor and Cerebellar Architectural Abnormalities during the Early Progression of Ataxia in a Mouse Model of SCA1 and How Early Prevention Leads to a Better Outcome Later in Life

Exposing developing cerebellar Purkinje neurons (PNs) to mutant Ataxin1 (ATXN1) in 82Q spinocerebellar ataxia type 1 (SCA1) mice disrupts motor behavior and cerebellar climbing fiber (CF) architecture from as early as 4 weeks of age. In contrast, if mutant ATXN1 expression is silenced until after cerebellar development is complete, then its impact on motor behavior and cerebellar architecture is greatly reduced. Under these conditions even 6 month old SCA1 mice exhibit largely intact motor behavior and molecular layer (ML) and CF architecture but show a modest reduction in PN soma area as a first sign of cerebellar disruption. Our results contrast the sensitivity of the developing cerebellum and remarkable resilience of the adult cerebellum to mutant ATXN1 and imply that SCA1 in this mouse model is both a developmental and neurodegenerative disorder.