title: 4-aminopyridine reverses ataxia and cerebellar firing deficiency in a mouse model of spinocerebellar ataxia type 6.
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 (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.
authors.affiliation: Department of Biology, McGill University, Montreal, H3G 0B1, Canada.|Integrated Program in Neuroscience, McGill University, Montreal, H3G 0B1, Canada.
authors.forename: Sriram
authors.initials: S
authors.lastname: Jayabal
authors.affiliation: Department of Physiology, McGill University, Montreal, H3G 1Y6, Canada.
authors.forename: Hui Ho Vanessa
authors.initials: HH
authors.lastname: Chang
authors.affiliation: Department of Physiology, McGill University, Montreal, H3G 1Y6, Canada.
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Cullen
authors.affiliation: Department of Biology, McGill University, Montreal, H3G 0B1, Canada.
authors.forename: Alanna J
authors.initials: AJ
authors.lastname: Watt
mesh_terms: D015761:4-Aminopyridine / Q000737:chemistry*; D000818:Animals; D002531:Cerebellum / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D004594:Electrophysiology; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity; D015221:Potassium Channels / Q000378:metabolism; D011689:Purkinje Cells / Q000378:metabolism; D020754:Spinocerebellar Ataxias / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism
chemical_list: D015221:Potassium Channels; D015761:4-Aminopyridine