Aminopyridines Correct Early Dysfunction and Delay Neurodegeneration in a Mouse Model of Spinocerebellar Ataxia Type 1
Open Access
- 17 August 2011
- journal article
- research article
- Published by Society for Neuroscience in Journal of Neuroscience
- Vol. 31 (33), 11795-11807
- https://doi.org/10.1523/jneurosci.0905-11.2011
Abstract
The contribution of neuronal dysfunction to neurodegeneration is studied in a mouse model of spinocerebellar ataxia type 1 (SCA1) displaying impaired motor performance ahead of loss or atrophy of cerebellar Purkinje cells. Presymptomatic SCA1 mice show a reduction in the firing rate of Purkinje cells (bothin vivoand in slices) associated with a reduction in the efficiency of the main glutamatergic synapse onto Purkinje cells and with increased A-type potassium current. The A-type potassium channel Kv4.3 appears to be internalized in response to glutamatergic stimulation in Purkinje cells and accumulates in presymptomatic SCA1 mice. SCA1 mice are treated with aminopyridines, acting as potassium channel blockers to test whether the treatment could improve neuronal dysfunction, motor behavior, and neurodegeneration. In acutely treated young SCA1 mice, aminopyridines normalize the firing rate of Purkinje cells and the motor behavior of the animals. In chronically treated old SCA1 mice, 3,4-diaminopyridine improves the firing rate of Purkinje cells, the motor behavior of the animals, and partially protects against cell atrophy. Chronic treatment with 3,4-diaminopyridine is associated with increased cerebellar levels of BDNF, suggesting that partial protection against atrophy of Purkinje cells is possibly provided by an increased production of growth factors secondary to the reincrease in electrical activity. Our data suggest that aminopyridines might have symptomatic and/or neuroprotective beneficial effects in SCA1, that reduction in the firing rate of Purkinje cells can cause cerebellar ataxia, and that treatment of early neuronal dysfunction is relevant in neurodegenerative disorders such as SCA1.Keywords
This publication has 45 references indexed in Scilit:
- The Therapeutic Mode of Action of 4-Aminopyridine in Cerebellar AtaxiaJournal of Neuroscience, 2010
- Aminopyridines Potentiate Synaptic and Neuromuscular Transmission by Targeting the Voltage-activated Calcium Channel β SubunitOnline Journal of Public Health Informatics, 2009
- Platelet-derived Growth Factor Selectively Inhibits NR2B-containing N-Methyl-D-aspartate Receptors in CA1 Hippocampal NeuronsOnline Journal of Public Health Informatics, 2009
- Protein Kinase A Mediates Activity-Dependent Kv4.2 Channel TraffickingJournal of Neuroscience, 2008
- The insulin-like growth factor pathway is altered in spinocerebellar ataxia type 1 and type 7Proceedings of the National Academy of Sciences of the United States of America, 2008
- Regulation of Dendritic Excitability by Activity-Dependent Trafficking of the A-Type K+ Channel Subunit Kv4.2 in Hippocampal NeuronsNeuron, 2007
- Purkinje cell dysfunction and alteration of long-term synaptic plasticity in fetal alcohol syndromeProceedings of the National Academy of Sciences of the United States of America, 2007
- Postsynaptic inositol 1,4,5-trisphosphate signaling maintains presynaptic function of parallel fiber–Purkinje cell synapses via BDNFProceedings of the National Academy of Sciences of the United States of America, 2006
- Distribution of brain‐derived neurotrophic factor and TrkB receptor proteins in the fetal and postnatal hippocampus and cerebellum of the guinea pigJournal of Comparative Neurology, 2002
- 3,4-Diaminopyridine in the Treatment of Lambert–Eaton Myasthenic SyndromeThe New England Journal of Medicine, 1989