FLUOXETINE ENHANCES TRKB EXPRESSION AND FUNCTION TO RESCUE MOTOR COORDINATION DEFICITS IN A MOUSE MODEL OF SPINOCEREBELLAR ATAXIA TYPE 6

Spinocerebellar ataxia type 6 (SCA6) is a rare, autosomal dominant neurodegenerative disease primarily affecting the cerebellum that leads to progressive problems with motor coordination and balance (ataxia) starting at midlife. While SCA6 significantly impairs a person’s quality of life, there are currently no available treatments to slow or stop this disease. We have previously shown that dysfunction in the expression and signalling of brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB) contributes to disease in a mouse model of SCA6. Intriguingly, fluoxetine (Prozac), an FDA-approved antidepressant, has recently been shown to act as an allosteric modulator of TrkB, facilitating BDNF-TrkB signaling. We thus wondered whether fluoxetine could mediate disease in SCA6 mice. We used a string-pull assay, in which mice engage in coordinated hand-over-hand movements, to assess motor coordination in treated and untreated SCA6 and litter-matched WT mice at disease onset (7.5 months). We observed that fluoxetine-treated SCA6 mice had a sustained and significant improvement in motor coordination, similar to WT levels, compared to untreated SCA6 mice. Using immunohistochemistry, we found that fluoxetine-treated SCA6 mice had significantly increased TrkB levels in the Purkinje cell soma compared to untreated SCA6 mice, while BDNF expression levels remained low. These findings suggest that fluoxetine is acting to enhance cerebellar TrkB expression and function in SCA6 mice. Our findings suggest that repurposing fluoxetine could provide a safe, affordable, and translatable treatment option for SCA6 and other ataxias where BDNF or TrkB signalling are affected.