Automated gait analysis indicates efficacy of T-type calcium channel inhibition for mitigation of disrupted calcium signalling in an SCA5 mouse model

Abstract

Spinocerebellar ataxias (SCAs) are dominantly inherited progressive neurodegenerative disorders which to date have no effective treatment. SCA5 arises from mutations in the β-III spectrin gene (SPTBN2) with mice lacking β-III spectrin function (β-III^-/-) mirroring the human clinical phenotype. This study finds evidence for dysregulated calcium homeostasis in β-III^-/- mice as evidenced by enhanced auto-phosphorylation of calcium-calmodulin dependent kinase II (CaMKII), a major calcium sensor in cells, and phosphorylation of several CaMKII targets. Mibefradil, an inhibitor of calcium channels, was also found to improve disordered β-III^-/- Purkinje cell dendritic morphology in vitro. However, key to evaluation of potential treatments in vivo is the ability to assess relevant changes at later stages of disease in β-III^-/- mice, which has previously been problematic. Here the CatWalk XT system was successful in detecting differences in both truncal stability and interlimb coordination across the disease course of β-III^-/- mice. Building on these findings CatWalk analysis showed trimethadione, a selective T-type calcium channel inhibitor, but not riluzole nor verapamil, significantly improved interlimb coordination of 8-month-old β-III^-/- mice. These findings highlight the CatWalk XT system as a valuable tool to assess age-dependence of motor function and that modulation of T-type calcium channels has therapeutic potential for SCAs.