Neuronal atrophy early in degenerative ataxia is a compensatory mechanism to regulate membrane excitability

James M. Dell’Orco, Aaron H. Wasserman, Ravi Chopra, Melissa A.C. Ingram, Yuan Shih Hu, Vikrant Singh, Heike Wulff, Puneet Opal, Harry T Orr, Vikram G. Shakkottai

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84 Scopus citations


Neuronal atrophy in neurodegenerative diseases is commonly viewed as an early event in a continuum that ultimately results in neuronal loss. In a mouse model of the polyglutamine disorder spinocerebellar ataxia type 1 (SCA1), we tested the hypothesis that cerebellar Purkinje neuron atrophy serves an adaptive role rather than being simply a nonspecific response to injury. In acute cerebellar slices from SCA1 mice, we find that Purkinje neuron pacemaker firing is initially normal but, with the onset of motor dysfunction, becomes disrupted, accompanied by abnormal depolarization. Remarkably, subsequent Purkinje cell atrophy is associated with a restoration of pacemaker firing. The early inability of Purkinje neurons to support repetitive spiking is due to unopposed calcium currents resulting from a reduction in large-conductance calcium-activated potassium (BK) and subthreshold-activated potassium channels. The subsequent restoration of SCA1 Purkinje neuron firing correlates with the recovery of the density of these potassium channels that accompanies cell atrophy. Supporting a critical role for BK channels, viral-mediated increases in BK channel expression in SCA1 Purkinje neurons improves motor dysfunction and partially restores Purkinje neuron morphology. Cerebellar perfusion of flufenamic acid, an agent that restores the depolarized membrane potential of SCA1 Purkinje neurons by activating potassium channels, prevents Purkinje neuron dendritic atrophy. These results suggest that Purkinje neuron dendritic remodeling in ataxia is an adaptive response to increases in intrinsic membrane excitability. Similar adaptive remodeling could apply to other vulnerable neuronal populations in neurodegenerative disease.

Original languageEnglish (US)
Pages (from-to)11292-11307
Number of pages16
JournalJournal of Neuroscience
Issue number32
StatePublished - Aug 12 2015

Bibliographical note

Publisher Copyright:
© 2015 the authors.


  • Ataxia
  • Atrophy
  • Cerebellum
  • Channel
  • Purkinje neuron
  • SCA1


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