Loss of Flocculus Purkinje Cell Firing Precision Leads to Impaired Gaze Stabilization in a Mouse Model of Spinocerebellar Ataxia Type 6 (SCA6)

• Published in: Cells (Basel, Switzerland) Vol. 11; no. 17; p. 2739
• Main Authors: Chang, Hui Ho Vanessa, Cook, Anna A, Watt, Alanna J, Cullen, Kathleen E
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.09.2022; MDPI
• Subjects: Animal models; Animals; Ataxia; CACNA1A protein; Calcium channels (voltage-gated); Cerebellum; Cerebellum - metabolism; Cytology; Development and progression; Disease Models, Animal; Eye movements; Firing pattern; Gaze; Genotype & phenotype; Health aspects; Mice; Morphology; motor learning; Motor skill learning; Mutation; Neurodegenerative diseases; Oculomotor behavior; optokinetic reflex; Optokinetic response; Phenotypes; Polyglutamine; Purkinje Cells; Rodents; saccades; Spinocerebellar ataxia; spinocerebellar ataxia type 6; Spinocerebellar Ataxias - genetics; Spinocerebellar Ataxias - metabolism; Spinocerebellar Degenerations - genetics; Trinucleotide repeat diseases; Trinucleotide repeats; Vestibulo-ocular reflex; vestibuloocular reflex; Canada; spinocerebellar ataxia type 6; eye movements; saccades; motor learning; optokinetic reflex; vestibuloocular reflex
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells11172739

Spinocerebellar Ataxia Type 6 (SCA6) is a mid-life onset neurodegenerative disease characterized by progressive ataxia, dysarthria, and eye movement impairment. This autosomal dominant disease is caused by the expansion of a CAG repeat tract in the gene that encodes the α1A subunit of the P/Q type voltage-gated Ca channel. Mouse models of SCA6 demonstrate impaired locomotive function and reduced firing precision of cerebellar Purkinje in the anterior vermis. Here, to further assess deficits in other cerebellar-dependent behaviors, we characterized the oculomotor phenotype of a knock-in mouse model with hyper-expanded polyQ repeats (SCA6 ). We found a reduction in the efficacy of the vestibulo-ocular reflex (VOR) and optokinetic reflex (OKR) in SCA6 mutant mice, without a change in phase, compared to their litter-matched controls. Additionally, VOR motor learning was significantly impaired in SCA6 mice. Given that the floccular lobe of the cerebellum plays a vital role in the generation of OKR and VOR calibration and motor learning, we investigated the firing behavior and morphology of floccular cerebellar Purkinje cells. Overall, we found a reduction in the firing precision of floccular lobe Purkinje cells but no morphological difference between SCA6 and wild-type mice. Taken together, our findings establish that gaze stabilization and motor learning are impaired in SCA6 mice and suggest that altered cerebellar output contributes to these deficits.