Synchronicity and Rhythmicity of Purkinje Cell Firing during Generalized Spike-and-Wave Discharges in a Natural Mouse Model of Absence Epilepsy.

Lieke Kros,Chris I De Zeeuw,Laurens W J Bosman,Sander Lindeman,Freek E Hoebeek,Oscar H J Eelkman Rooda,Pavithra Murugesan,Lorenzo Bina

doi:10.3389/fncel.2017.00346

Abstract

Absence epilepsy is characterized by the occurrence of generalized spike and wave discharges (GSWDs) in electrocorticographical (ECoG) recordings representing oscillatory activity in thalamocortical networks. The oscillatory nature of GSWDs has been shown to be reflected in the simple spike activity of cerebellar Purkinje cells and in the activity of their target neurons in the cerebellar nuclei, but it is unclear to what extent complex spike activity is implicated in generalized epilepsy. Purkinje cell complex spike firing is elicited by climbing fiber activation and reflects action potential firing in the inferior olive. Here, we investigated to what extent modulation of complex spike firing is reflected in the temporal patterns of seizures. Extracellular single-unit recordings in awake, head-restrained homozygous tottering mice, which suffer from a mutation in the voltage-gated CaV2.1 calcium channel, revealed that a substantial proportion of Purkinje cells (26%) showed increased complex spike activity and rhythmicity during GSWDs. Moreover, Purkinje cells, recorded either electrophysiologically or by using Ca2+-imaging, showed a significant increase in complex spike synchronicity for both adjacent and remote Purkinje cells during ictal events. These seizure-related changes in firing frequency, rhythmicity and synchronicity were most prominent in the lateral cerebellum, a region known to receive cerebral input via the inferior olive. These data indicate profound and widespread changes in olivary firing that are most likely induced by seizure-related activity changes in the thalamocortical network, thereby highlighting the possibility that olivary neurons can compensate for pathological brain-state changes by dampening oscillations.

Highlights

Absence epilepsy is a common form of generalized epilepsy that clinically manifests itself as behavioral arrest and diminished consciousness (Snead, 1995; Andermann and Berkovic, 2001; Norden and Blumenfeld, 2002; Fisher et al, 2014)
To establish to what extent activity of the inferior olive and the cerebellar Purkinje cells contribute to the oscillatory activity of cerebellar nuclei neurons during absence seizures, we investigated temporal relations of complex spike and simple spike firing patterns with generalized spike and wave discharges (GSWDs)
These ECoG recordings revealed GSWDs, which are characterized by negative deflections that occur at a mean frequency of 7.74 ± 1.01 Hz (N = 23)

Summary

Introduction

Absence epilepsy is a common form of generalized epilepsy that clinically manifests itself as behavioral arrest and diminished consciousness (Snead, 1995; Andermann and Berkovic, 2001; Norden and Blumenfeld, 2002; Fisher et al, 2014). It is characterized by thalamocortical network oscillations occurring as generalized spike and wave discharges (GSWDs) in electrocorticographical (ECoG) recordings. Likewise the simple spike activity of Purkinje cells in the cerebellar cortex can be phase-locked to the GSWDs (Kandel and Buzsáki, 1993; Kros et al, 2015b)

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