Objective: To evaluate the effectiveness of Deep Brain Stimulation (DBS) in a mouse model of Spinocerebellar Ataxia type 1 (SCA1).

Background: Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominantly inherited neurodegenerative disorder resulting in Purkinje cell loss and atrophy of the brainstem and cerebellum. There is no cure for SCA1 and typically, symptoms worsen over time and death results from complications related to brainstem dysfunction. An absence of the inhibitory signals to the deep cerebellar nuclei (DCN) is postulated to result in hyperexcitability and disinhibition of DCN neurons thereby affecting the cerebellar-thalamic-cortical pathways. Regulating firing frequency of DCN neurons could potentially ameliorate symptoms of the disease. We hypothesize that DBS can be used to alleviate ataxia in SCA1 mice. 

Methods: Symptomatic B05/SCA1 mice were stereotactically implanted in the DCN with stainless steel, single channel, DBS electrodes (Plastics One). Mice in the experimental “STIM” group underwent acute High Frequency Stimulation (HFS) for one week post recovery and mice in the “SHAM” group did not undergo any HFS. Mice were tested for improvements in gait by comparing gait signal before DBS implantation, after DBS implantation and again after HFS. At the end of the experimental paradigm, mice were sacrificed, brains dissected and flash frozen for transcriptomic analyses to assess gene expression changes occurring from HFS. 

Results: We were able to implant DBS electrodes in DCN of B05 mice and perform acute HFS. Gait assessment of movement control and coordination demonstrated improvements in the experimental group of mice following HFS DBS. Hind paw area and power generation of the hind paw during propulsion (MAX dA/dT) was returned to values similar to wild-type siblings. This implies that our treatment at least corrects B05 mice for their lack of control and deceleration. Transcriptomic analysis is ongoing.

Conclusions: In this study, we were able to target the deep cerebellar nucleus in ataxic mice with DBS electrodes and perform acute HFS. We demonstrate improvement in the gait of stimulated animals. Further work including chronic stimulation paradigms will be necessary to confirm our initial observations in order to translate this therapy to humans.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/effectiveness-of-deep-brain-stimulation-dbs-in-mice-with-spinocerebellar-ataxia-sca1/