Stimulation of Purkinje cell firing reverses early onset spatial navigation deficits in a spinocerebellar ataxia type 6 mouse model

Spinocerebellar ataxia type 6 (SCA6) is a hereditary neurodegenerative disease that manifests in a late onset and progressive impairment of motor coordination, balance and speech as well as cerebellar and brainstem atrophy. It is caused by a polyglutamine expansion in the CACNA1A gene which bicistronically encodes the α1A-subunit of the P/Q-type voltage-gated calcium channel and the transcription factor α1ACT. The lack of treatments for SCA6 patients emphasizes the necessity to investigate the underlying pathomechanisms and its impact on cognition. In this study we found that SCA6 mice demonstrate spatial navigation deficits which precede their motor deficiencies. This resulted in a concomitant Purkinje cell (PC) dysfunction, exhibited by a disruption in their PC spontaneous simple spike firing rates and regularity of firing. PC dysfunction was further confirmed by elevated numbers of axonal swellings found in the PC proximal axons throughout the cerebellum. More importantly, we were able to partially rescue irregular PC firing and spatial navigation deficits using a stimulatory Gq-protein coupled designer receptor exclusively activated by a designer drug (Gq-DREADD), further indicating that PC dysfunction contributes to SCA6 cognitive abnormalities in spatial navigation.