CaV3.1 is a tremor rhythm pacemaker in the inferior olive

Young Gyun Park, Hye Yeon Park, Changjoon Lee, Soonwook Choi, Seonmi Jo, Hansol Choi, Yang Hann Kim, Hee Sup Shin, Rodolfo R. Llinas, Daesoo Kim

Research output: Contribution to journalArticle

78 Citations (Scopus)

Abstract

The rhythmic motor pathway activation by pacemaker neurons or circuits in the brain has been proposed as the mechanism for the timing of motor coordination, and the abnormal potentiation of this mechanism may lead to a pathological tremor. Here, we show that the potentiation of CaV3.1 T-type Ca2+ channels in the inferior olive contributes to the onset of the tremor in a pharmacological model of essential tremor. After administration of harmaline, 4- to 10-Hz synchronous neuronal activities arose from the IO and then propagated to cerebellar motor circuits in wild-type mice, but those rhythmic activities were absent in mice lacking CaV3.1 gene. Intracellular recordings in brain-stem slices revealed that the Ca V3.1-deficient inferior olive neurons lacked the subthreshold oscillation of membrane potentials and failed to trigger 4- to 10-Hz rhythmic burst discharges in the presence of harmaline. In addition, the selective knockdown of CaV3.1 gene in the inferior olive by shRNA efficiently suppressed the harmaline-induced tremor in wild-type mice. A mathematical model constructed based on data obtained from patch-clamping experiments indicated that harmaline could efficiently potentiate CaV3.1 channels by changing voltage-dependent responsiveness in the hyperpolarizing direction. Thus, CaV3.1 is a molecular pacemaker substrate for intrinsic neuronal oscillations of inferior olive neurons, and the potentiation of this mechanism can be considered as a pathological cause of essential tremor.

Original languageEnglish
Pages (from-to)10731-10736
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number23
DOIs
Publication statusPublished - 2010 Jun 8
Externally publishedYes

Fingerprint

Harmaline
Tremor
Essential Tremor
Neurons
Gene Knockdown Techniques
Efferent Pathways
Constriction
Membrane Potentials
Small Interfering RNA
Brain Stem
Theoretical Models
Pharmacology
Brain
Genes

Keywords

  • Harmaline
  • Subthreshold oscillation
  • T-type calcium channel

ASJC Scopus subject areas

  • General

Cite this

CaV3.1 is a tremor rhythm pacemaker in the inferior olive. / Park, Young Gyun; Park, Hye Yeon; Lee, Changjoon; Choi, Soonwook; Jo, Seonmi; Choi, Hansol; Kim, Yang Hann; Shin, Hee Sup; Llinas, Rodolfo R.; Kim, Daesoo.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 23, 08.06.2010, p. 10731-10736.

Research output: Contribution to journalArticle

Park, YG, Park, HY, Lee, C, Choi, S, Jo, S, Choi, H, Kim, YH, Shin, HS, Llinas, RR & Kim, D 2010, 'CaV3.1 is a tremor rhythm pacemaker in the inferior olive', Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 23, pp. 10731-10736. https://doi.org/10.1073/pnas.1002995107
Park, Young Gyun ; Park, Hye Yeon ; Lee, Changjoon ; Choi, Soonwook ; Jo, Seonmi ; Choi, Hansol ; Kim, Yang Hann ; Shin, Hee Sup ; Llinas, Rodolfo R. ; Kim, Daesoo. / CaV3.1 is a tremor rhythm pacemaker in the inferior olive. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 23. pp. 10731-10736.
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