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

Sriram Jayabal,Kathleen E Cullen,Hui Ho Vanessa Chang,Alanna J Watt

doi:10.1038/srep29489

Sriram Jayabal, Kathleen E Cullen + Show 2 more

Open Access

https://doi.org/10.1038/srep29489

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Journal: Scientific Reports	Publication Date: Jul 6, 2016
Citations: 88	License type: CC BY 4.0

Affiliation: McGill University

Abstract

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 (SCA684Q/+) 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 (SCA684Q/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 SCA684Q/84Q mice both in acute slices and in vivo. These results provide a novel therapeutic approach for treating ataxic symptoms associated with SCA6.

Highlights

Alterations in Purkinje cell firing precision can be detected in heterozygous mice at 19 months, when motor deficits were observed[6]
Using a mouse model of SCA6 harboring a humanized CACNA1A gene encoding a hyper-expanded (84Q) repeat[6], we explored the cellular pathophysiology underlying the onset of ataxia
These results suggest that changes in the precision of action potential timing occur in SCA6 mice when motor coordination deficits are present

Summary

Introduction

Alterations in Purkinje cell firing precision can be detected in heterozygous mice at 19 months, when motor deficits were observed[6]. Similar alterations in firing precision were seen in homozygous mice at 7 months, when motor deficits were observed in these mice[6,10], demonstrating common pathophysiology for homozygous and heterozygous SCA684Q mice in a gene dose-age dependent manner. We show that chronic oral administration of 4-AP rescues ataxic symptoms in SCA684Q/84Q mice, and that this rescue is associated with a recovery of Purkinje cell firing precision. These findings suggest a first pharmacological approach for treating SCA6

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Results

Conclusion