4-aminopyridine Reverses Ataxia and Cerebellar Firing Deficiency in a Mouse Model of Spinocerebellar Ataxia Type 6

Overview

Journal Sci Rep

Specialty Science

Date 2016 Jul 7

PMID 27381005

Citations 56

Authors

Sriram Jayabal

Hui Ho Vanessa Chang

Kathleen E Cullen

Alanna J Watt

Affiliations

Soon will be listed here.

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.

Citing Articles

Balance Performance in Aged Mice is Dependent on Unipolar Brush Cells.

Kizeev G, Witteveen I, Balmer T Cerebellum. 2024; 24(1):16.

PMID: 39699796 DOI: 10.1007/s12311-024-01767-x.

Balance performance in aged mice is dependent on unipolar brush cells.

Kizeev G, Witteveen I, Balmer T bioRxiv. 2024; .

PMID: 39416048 PMC: 11482929. DOI: 10.1101/2024.10.10.617602.

Ablation of TrkB from Enkephalinergic Precursor-Derived Cerebellar Granule Cells Generates Ataxia.

Eliseeva E, Malik M, Minichiello L Biology (Basel). 2024; 13(8).

PMID: 39194574 PMC: 11351323. DOI: 10.3390/biology13080637.

Downbeat nystagmus: a clinical and pathophysiological review.

Marcelli V, Giannoni B, Volpe G, Faralli M, Fetoni A, Pettorossi V Front Neurol. 2024; 15:1394859.

PMID: 38854962 PMC: 11157062. DOI: 10.3389/fneur.2024.1394859.

A combination of chlorzoxazone and folic acid improves recognition memory, anxiety and depression in SCA3-84Q mice.

Marinina K, Bezprozvanny I, Egorova P Hum Mol Genet. 2024; 33(16):1406-1419.

PMID: 38727562 PMC: 11305683. DOI: 10.1093/hmg/ddae079.

References

Womack M, Chevez C, Khodakhah K . Calcium-activated potassium channels are selectively coupled to P/Q-type calcium channels in cerebellar Purkinje neurons. J Neurosci. 2004; 24(40):8818-22. PMC: 6729958. DOI: 10.1523/JNEUROSCI.2915-04.2004. View

Watase K, Barrett C, Miyazaki T, Ishiguro T, Ishikawa K, Hu Y . Spinocerebellar ataxia type 6 knockin mice develop a progressive neuronal dysfunction with age-dependent accumulation of mutant CaV2.1 channels. Proc Natl Acad Sci U S A. 2008; 105(33):11987-92. PMC: 2503926. DOI: 10.1073/pnas.0804350105. View

Zhuchenko O, Bailey J, Bonnen P, Ashizawa T, Stockton D, Amos C . Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel. Nat Genet. 1997; 15(1):62-9. DOI: 10.1038/ng0197-62. View

DellOrco J, Wasserman A, Chopra R, Ingram M, Hu Y, Singh V . Neuronal Atrophy Early in Degenerative Ataxia Is a Compensatory Mechanism to Regulate Membrane Excitability. J Neurosci. 2015; 35(32):11292-307. PMC: 4532759. DOI: 10.1523/JNEUROSCI.1357-15.2015. View

Yang Q, Hashizume Y, Yoshida M, Wang Y, Goto Y, Mitsuma N . Morphological Purkinje cell changes in spinocerebellar ataxia type 6. Acta Neuropathol. 2000; 100(4):371-6. DOI: 10.1007/s004010000201. View

Strittmatter S . Overcoming Drug Development Bottlenecks With Repurposing: Old drugs learn new tricks. Nat Med. 2014; 20(6):590-1. PMC: 4371131. DOI: 10.1038/nm.3595. View

Possidente B, Birnbaum S . Circadian rhythms for food and water consumption in the mouse, Mus musculus. Physiol Behav. 1979; 22(4):657-60. DOI: 10.1016/0031-9384(79)90226-9. View

Shakkottai V, Costa M, DellOrco J, Sankaranarayanan A, Wulff H, Paulson H . Early changes in cerebellar physiology accompany motor dysfunction in the polyglutamine disease spinocerebellar ataxia type 3. J Neurosci. 2011; 31(36):13002-14. PMC: 3170039. DOI: 10.1523/JNEUROSCI.2789-11.2011. View

Strupp M, Kalla R, Freilinger T, Dichgans M, Brandt T . Dysfunction of the brain calcium channel CaV2.1 in absence epilepsy and episodic ataxia--a comment. Brain. 2005; 128(Pt 6):E32. DOI: 10.1093/brain/awh440. View

10.

Llinas R, Sugimori M . Electrophysiological properties of in vitro Purkinje cell dendrites in mammalian cerebellar slices. J Physiol. 1980; 305:197-213. PMC: 1282967. DOI: 10.1113/jphysiol.1980.sp013358. View

11.

Walter J, Alvina K, Womack M, Chevez C, Khodakhah K . Decreases in the precision of Purkinje cell pacemaking cause cerebellar dysfunction and ataxia. Nat Neurosci. 2006; 9(3):389-97. DOI: 10.1038/nn1648. View

12.

Hourez R, Servais L, Orduz D, Gall D, Millard I, de Kerchove dExaerde A . Aminopyridines correct early dysfunction and delay neurodegeneration in a mouse model of spinocerebellar ataxia type 1. J Neurosci. 2011; 31(33):11795-807. PMC: 6623197. DOI: 10.1523/JNEUROSCI.0905-11.2011. View

13.

Hausser M, Clark B . Tonic synaptic inhibition modulates neuronal output pattern and spatiotemporal synaptic integration. Neuron. 1997; 19(3):665-78. DOI: 10.1016/s0896-6273(00)80379-7. View

14.

Mark M, Krause M, Boele H, Kruse W, Pollok S, Kuner T . Spinocerebellar ataxia type 6 protein aggregates cause deficits in motor learning and cerebellar plasticity. J Neurosci. 2015; 35(23):8882-95. PMC: 6605201. DOI: 10.1523/JNEUROSCI.0891-15.2015. View

15.

Bever Jr C, Young D, Anderson P, Krumholz A, Conway K, Leslie J . The effects of 4-aminopyridine in multiple sclerosis patients: results of a randomized, placebo-controlled, double-blind, concentration-controlled, crossover trial. Neurology. 1994; 44(6):1054-9. DOI: 10.1212/wnl.44.6.1054. View

16.

Du X, Wang J, Zhu H, Rinaldo L, Lamar K, Palmenberg A . Second cistron in CACNA1A gene encodes a transcription factor mediating cerebellar development and SCA6. Cell. 2013; 154(1):118-33. PMC: 3939801. DOI: 10.1016/j.cell.2013.05.059. View

17.

Solodkin A, Gomez C . Spinocerebellar ataxia type 6. Handb Clin Neurol. 2011; 103:461-73. DOI: 10.1016/B978-0-444-51892-7.00029-2. View

18.

Inoue T, Lin X, Kohlmeier K, Orr H, Zoghbi H, Ross W . Calcium dynamics and electrophysiological properties of cerebellar Purkinje cells in SCA1 transgenic mice. J Neurophysiol. 2001; 85(4):1750-60. DOI: 10.1152/jn.2001.85.4.1750. View

19.

Matsumura R, Futamura N, Fujimoto Y, Yanagimoto S, Horikawa H, Suzumura A . Spinocerebellar ataxia type 6. Molecular and clinical features of 35 Japanese patients including one homozygous for the CAG repeat expansion. Neurology. 1997; 49(5):1238-43. DOI: 10.1212/wnl.49.5.1238. View

20.

Goodman A, Brown T, Krupp L, Schapiro R, Schwid S, Cohen R . Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial. Lancet. 2009; 373(9665):732-8. DOI: 10.1016/S0140-6736(09)60442-6. View