Disruption of the olivo-cerebellar circuit by Purkinje neuron-specific ablation of BK channels

Xiaowei Chena, Yury Kovalchuka, Helmuth Adelsberger, Horst A. Henning, Matthias Sausbierb, Georg Wietzorrek, Peter Ruth, Yosef Yarom, Arthur Konnerth

Research output: Contribution to journalArticlepeer-review

84 Scopus citations

Abstract

The large-conductance voltage- and calcium-activated potassium (BK) channels are ubiquitously expressed in the brain and play an important role in the regulation of neuronal excitation. Previous work has shown that the total deletion of these channels causes an impaired motor behavior, consistent with a cerebellar dysfunction. Cellular analyses showed that a decrease in spike firing rate occurred in at least two types of cerebellar neurons, namely in Purkinje neurons (PNs) and in Golgi cells. To determine the relative role of PNs, we developed a cell-selective mouse mutant, which lacked functional BK channels exclusively in PNs. The behavioral analysis of these mice revealed clear symptoms of ataxia, indicating that the BK channels of PNs are of major importance for normal motor coordination. By using combined two-photon imaging and patch-clamp recordings in these mutant mice, we observed a unique type of synaptic dysfunction in vivo, namely a severe silencing of the climbing fiber - evoked complex spike activity. By performing targeted pharmacological manipulations combined with simultaneous patch-clamp recordings in PNs, we obtained direct evidence that this silencing of climbing fiber activity is due to a malfunction of the tripartite olivo-cerebellar feedback loop, consisting of the inhibitory synaptic connection of PNs to the deep cerebellar nuclei (DCN), followed by a projection of inhibitory DCN afferents to the inferior olive, the origin of climbing fibers. Taken together, our results establish an essential role of BK channels of PNs for both cerebellar motor coordination and feedback regulation in the olivo-cerebellar loop.

Original languageEnglish
Pages (from-to)12323-12328
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number27
DOIs
StatePublished - 6 Jul 2010

Keywords

  • Cerebellar ataxia
  • Climbing fiber
  • Complex spike
  • Two-photon imaging

Fingerprint

Dive into the research topics of 'Disruption of the olivo-cerebellar circuit by Purkinje neuron-specific ablation of BK channels'. Together they form a unique fingerprint.

Cite this