Controlling absence seizures from the cerebellar nuclei via activation of the Gq signaling pathway

Jan Claudius Schwitalla, Johanna Pakusch, Brix Mücher, Alexander Brückner, Dominic Alexej Depke, Thomas Fenzl, Chris I De Zeeuw, Lieke Kros, Freek E Hoebeek, Melanie D Mark

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Absence seizures (ASs) are characterized by pathological electrographic oscillations in the cerebral cortex and thalamus, which are called spike-and-wave discharges (SWDs). Subcortical structures, such as the cerebellum, may well contribute to the emergence of ASs, but the cellular and molecular underpinnings remain poorly understood. Here we show that the genetic ablation of P/Q-type calcium channels in cerebellar granule cells (quirky) or Purkinje cells (purky) leads to recurrent SWDs with the purky model showing the more severe phenotype. The quirky mouse model showed irregular action potential firing of their cerebellar nuclei (CN) neurons as well as rhythmic firing during the wave of their SWDs. The purky model also showed irregular CN firing, in addition to a reduced firing rate and rhythmicity during the spike of the SWDs. In both models, the incidence of SWDs could be decreased by increasing CN activity via activation of the Gq-coupled designer receptor exclusively activated by designer drugs (DREADDs) or via that of the Gq-coupled metabotropic glutamate receptor 1. In contrast, the incidence of SWDs was increased by decreasing CN activity via activation of the inhibitory Gi/o-coupled DREADD. Finally, disrupting CN rhythmic firing with a closed-loop channelrhodopsin-2 stimulation protocol confirmed that ongoing SWDs can be ceased by activating CN neurons. Together, our data highlight that P/Q-type calcium channels in cerebellar granule cells and Purkinje cells can be relevant for epileptogenesis, that Gq-coupled activation of CN neurons can exert anti-epileptic effects and that precisely timed activation of the CN can be used to stop ongoing SWDs.

Originele taal-2Engels
Pagina's (van-tot)197
TijdschriftCellular and Molecular Life Sciences
Volume79
Nummer van het tijdschrift4
DOI's
StatusGepubliceerd - mrt. 2022

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