Reduced cerebellar Gq-protein signaling elicits early onset spatial navigation deficits in a SCA6 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 1A-subunit of the P/Q-type voltage-gated calcium channel and the transcription factor 1ACT. To date, no effective treatment exists and the exact pathobiology is controversially discussed; especially the impact on cognition is poorly understood. Here, we demonstrate that SCA6 84Q mice exhibit cognitive deficits in their spatial navigation abilities. Surprisingly, spatial memory impairments develop prior to motor impairments at 5 months of age. By expressing and stimulating a Gq-protein coupled designer receptor exclusively activated by a designer drug (Gq-DREADD) in the cerebellum, we were able to counteract these spatial navigation deficits indicating that a reduced Gq-protein signaling is part of the SCA6 phenotype. Electrophysiological recordings in anaesthetized mice further revealed that Purkinje cells (PCs) of SCA6 84Q mice exhibit a disrupted spontaneous simple spike activity that precedes the development of both cognitive and motor deficits. Concurrently, PC dysfunction was further confirmed by elevated numbers of torpedoes found in the proximal axon of PCs throughout the cerebellum. Overall, our study raises awareness to survey cognitive abnormalities more carefully during clinical examination to detect the disease earlier and potentially optimize the individual treatment by enhancing PC signaling. Significance statementSCA6 is a hereditary neurological disease that is mainly characterized by the late-onset development of progressive motor deficits. Here we show, using a SCA6 mouse model, that cognitive impairments in spatial navigation are also a non-negligible feature of the disease which manifests earlier than the motor deficits. Moreover, we demonstrate that these spatial navigation deficits are caused by a reduced Gq-protein signaling in the cerebellum. Electrophysiological and histological analysis further confirmed dysfunctional PC signaling even before the onset of first symptoms. Since no effective treatment is available for SCA6 patients, early onset stimulation of PC signaling may be a new therapeutic approach.