Purkinje cell BKchannel ablation induces abnormal rhythm in deep cerebellar nuclei and prevents LTD

Guy Cheron,Claudia Ammann,Cynthia Prigogine,Peter Ruth,Javier Márquez-Ruiz,Julian Cheron,Robert Lukowski,Bernard Dan

doi:10.1038/s41598-018-22654-6

Guy Cheron, Claudia Ammann + Show 6 more

Open Access

https://doi.org/10.1038/s41598-018-22654-6

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Abstract

Purkinje cells (PC) control deep cerebellar nuclei (DCN), which in turn inhibit inferior olive nucleus, closing a positive feedback loop via climbing fibers. PC highly express potassium BK channels but their contribution to the olivo-cerebellar loop is not clear. Using multiple-unit recordings in alert mice we found in that selective deletion of BK channels in PC induces a decrease in their simple spike firing with a beta-range bursting pattern and fast intraburst frequency (~200 Hz). To determine the impact of this abnormal rhythm on the olivo-cerebellar loop we analyzed simultaneous rhythmicity in different cerebellar structures. We found that this abnormal PC rhythmicity is transmitted to DCN neurons with no effect on their mean firing frequency. Long term depression at the parallel-PC synapses was altered and the intra-burst complex spike spikelets frequency was increased without modification of the mean complex spike frequency in BK-PC−/− mice. We argue that the ataxia present in these conditional knockout mice could be explained by rhythmic disruptions transmitted from mutant PC to DCN but not by rate code modification only. This suggests a neuronal mechanism for ataxia with possible implications for human disease.

Highlights

BK channels are large-conductance voltage and Ca2+-activated K+ channels acting as important signals modulators in many types of neurons[1,2,3]
If there is a functional link between increased rhythmicity and ataxia[21], (1) selective suppression of Purkinje cells (PC)-BK channels should produce abnormal rhythmicity in the cerebellar cortex and (2) this abnormal rhythm should be transmitted to the deep cerebellar nuclei (DCN)
In order to highlight the potential role of PC-BK channels in the sensory-stimulation plasticity observed in the cerebellar cortex of WT alert mice[36], we investigated the local field potentials (LFP) plasticity recorded in the Crus I or Crus II area, evoked by electrical stimulation of the whisker pad

Summary

Introduction

BK channels are large-conductance voltage and Ca2+-activated K+ channels acting as important signals modulators in many types of neurons[1,2,3] They are activated by the conjunction of membrane depolarization and intracellular Ca2+ concentration ([Ca2+]i), and yield strong K+ currents. The BK channel could play a key role in PC by limiting Ca2+ entrance during CF input[18] This tight regulation underlies crucial Ca2+ functions in neuronal excitability and plasticity. The precise role played by the PC-BK channels has not been elucidated in the alert state In this perspective, the generation of a mouse line with a PC-specific deletion of BK channels (PC-BK−/−) offers an ideal model for studying the PC-BK channels’ role in cerebellar physiology. The temporal pattern of PC firing is highly dependent on alertness[32,33,34]

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