Abnormal high-frequency burst firing of cerebellar neurons in rapid-onset dystonia-parkinsonism

Rachel Fremont, D. Paola Calderon, Sara Maleki, Kamran Khodakhah

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Loss-of-function mutations in the α3 isoform of the Na+/K+ ATPase (sodium pump) are responsible for rapid-onset dystonia parkinsonism (DYT12). Recently, a pharmacological model of DYT12 was generated implicating both the cerebellum and basal ganglia in the disorder. Notably, partially blocking sodium pumps in the cerebellum was necessary and sufficient for induction of dystonia. Thus, a key question that remains is how partially blocking sodium pumps in the cerebellum induces dystonia. In vivo recordings from dystonic mice revealed abnormal high-frequency bursting activity in neurons of the deep cerebellar nuclei (DCN), which comprise the bulk of cerebellar output. In the same mice, Purkinje cells, which provide strong inhibitory drive to DCN cells, also fired in a similarly erratic manner. In vitro studies demonstrated that Purkinje cells are highly sensitive to sodium pump dysfunction that alters the intrinsic pacemaking of these neurons, resulting in erratic burst firing similar to that identified in vivo. This abnormal firing abates when sodium pump function is restored and dystonia caused by partial block of sodium pumps can be similarly alleviated. These findings suggest that persistent high-frequency burst firing of cerebellar neurons caused by sodium pump dysfunction underlies dystonia in this model of DYT12.

Original languageEnglish (US)
Pages (from-to)11723-11732
Number of pages10
JournalJournal of Neuroscience
Volume34
Issue number35
DOIs
StatePublished - Aug 27 2014

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Sodium-Potassium-Exchanging ATPase
Dystonia
Neurons
Cerebellum
Cerebellar Nuclei
Purkinje Cells
Basal Ganglia Diseases
Dystonia 12
Protein Isoforms
Pharmacology
Mutation

Keywords

  • Basal ganglia
  • Cerebellum

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Abnormal high-frequency burst firing of cerebellar neurons in rapid-onset dystonia-parkinsonism. / Fremont, Rachel; Paola Calderon, D.; Maleki, Sara; Khodakhah, Kamran.

In: Journal of Neuroscience, Vol. 34, No. 35, 27.08.2014, p. 11723-11732.

Research output: Contribution to journalArticle

Fremont, Rachel ; Paola Calderon, D. ; Maleki, Sara ; Khodakhah, Kamran. / Abnormal high-frequency burst firing of cerebellar neurons in rapid-onset dystonia-parkinsonism. In: Journal of Neuroscience. 2014 ; Vol. 34, No. 35. pp. 11723-11732.
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