4-aminopyridine reverses ataxia and cerebellar firing deficiency in a mouse model of spinocerebellar ataxia type 6

• Published in: Scientific reports Vol. 6; no. 1; p. 29489
• Main Authors: Jayabal, Sriram, Chang, Hui Ho Vanessa, Cullen, Kathleen E., Watt, Alanna J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.07.2016; Nature Publishing Group
• Subjects: 631/378/1689/2014; Ataxia; Cells; Disease; Humanities and Social Sciences; Motor ability; multidisciplinary; Pacemakers; Pathophysiology; Science
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep29489

Spinocerebellar ataxia type 6 (SCA6) is a devastating midlife-onset autosomal dominant motor control disease with no known treatment. Using a hyper-expanded polyglutamine (84Q) knock-in mouse, we found that cerebellar Purkinje cell firing precision was degraded in heterozygous (SCA6 84Q/+ ) mice at 19 months when motor deficits are observed. Similar alterations in firing precision and motor control were observed at disease onset at 7 months in homozygous (SCA6 84Q/84Q ) mice, as well as a reduction in firing rate. We further found that chronic administration of the FDA-approved drug 4-aminopyridine (4-AP), which targets potassium channels, alleviated motor coordination deficits and restored cerebellar Purkinje cell firing precision to wildtype (WT) levels in SCA6 84Q/84Q mice both in acute slices and in vivo . These results provide a novel therapeutic approach for treating ataxic symptoms associated with SCA6.