Cerebellar deep brain stimulation rescues Purkinje cell mitochondrial density in a genetic mouse model of cerebellar ataxia

Deep brain stimulation (DBS) improves motor function in a growing list of movement diseases including Parkinson's disease, dystonia, and tremor. There is evidence that DBS may also be effective in ataxia. It is not known why DBS is effective, but modulating cell activity and conferring neuroprotection are hypothesized to underlie its benefits. Understanding the effects of DBS on neurons is paramount to extending its clinical use in the treatment of various motor and non-motor diseases. Here, we stimulated the cerebellum of Car8 waddles (Car8^wdl) mice, given the cerebellum's important role in ataxia pathophysiology. Using transmission electron microscopy, we tested the effects of therapeutic neuromodulation on Purkinje cell subcellular structures, including the mitochondria and their proximity to the endoplasmic reticulum (ER). In the absence of stimulation, we found increased putative mitochondria-ER contacts in Car8^wdl Purkinje cells as well as mitochondrial size and density alterations. Low-frequency cerebellar DBS rescued mitochondrial density, but not size or putative contacts in Car8^wdl Purkinje cells. Although increased mitochondrial density and sustained ER contact are specific to DBS treatment, they do not determine efficaciousness. These data uncover a mode of intracellular plasticity in Purkinje cells after stimulation, enhancing our mechanistic understanding of DBS for cerebellar disorders.