35
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      Potassium channel dysfunction underlies Purkinje neuron spiking abnormalities in spinocerebellar ataxia type 2

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Alterations in Purkinje neuron firing often accompany ataxia, but the molecular basis for these changes is poorly understood. In a mouse model of spinocerebellar ataxia type 2 (SCA2), a progressive reduction in Purkinje neuron firing frequency accompanies cell atrophy. We investigated the basis for altered Purkinje neuron firing in SCA2. A reduction in the expression of large-conductance calcium-activated potassium (BK) channels and Kv3.3 voltage-gated potassium channels accompanies the inability of Purkinje neurons early in disease to maintain repetitive spiking. In association with prominent Purkinje neuron atrophy, repetitive spiking is restored, although at a greatly reduced firing frequency. In spite of a continued impairment in spike repolarization and a persistently reduced BK channel mediated afterhyperpolarization (AHP), repetitive spiking is maintained, through the increased activity of barium-sensitive potassium channels, most consistent with inwardly rectifying potassium (K ir) channels. Increased activity of K ir channels results in the generation of a novel AHP not seen in wild-type Purkinje neurons that also accounts for the reduced firing frequency late in disease. Homeostatic changes in Purkinje neuron morphology that help to preserve repetitive spiking can also therefore have deleterious consequences for spike frequency. These results suggest that the basis for spiking abnormalities in SCA2 differ depending on disease stage, and interventions targeted towards correcting potassium channel dysfunction in ataxia need to be tailored to the specific stage in the degenerative process.

          Related collections

          Author and article information

          Journal
          Hum Mol Genet
          Hum. Mol. Genet
          hmg
          Human Molecular Genetics
          Oxford University Press
          0964-6906
          1460-2083
          15 October 2017
          17 July 2017
          15 October 2018
          : 26
          : 20
          : 3935-3945
          Affiliations
          [1 ]Department of Neurology, University of Michigan Medical School, Ann Arbor, MI 48103, USA
          [2 ]Department of Neurology, University of Utah, Salt Lake City, UT 84112, USA
          [3 ]Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA
          Author notes
          [* ]To whom correspondence should be addressed at: Department of Neurology, University of Michigan, 4009 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109, USA. Tel: 734 6156891; Fax: 734 6479777; Email: vikramsh@ 123456med.umich.edu
          Article
          PMC5886219 PMC5886219 5886219 ddx281
          10.1093/hmg/ddx281
          5886219
          29016852
          ac397747-fdb1-4e74-9841-b1275acbca53
          © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com
          History
          : 21 April 2017
          : 10 July 2017
          : 13 July 2017
          Page count
          Pages: 11
          Funding
          Funded by: National Institute of Neurological Disorders and Stroke 10.13039/100000065
          Award ID: NIH R01NS085054
          Categories
          Articles

          Comments

          Comment on this article

          scite_
          0
          0
          0
          0
          Smart Citations
          0
          0
          0
          0
          Citing PublicationsSupportingMentioningContrasting
          View Citations

          See how this article has been cited at scite.ai

          scite shows how a scientific paper has been cited by providing the context of the citation, a classification describing whether it supports, mentions, or contrasts the cited claim, and a label indicating in which section the citation was made.

          Similar content288

          Cited by27