Controlling absence seizures from the cerebellar nuclei via activation of the Gq signaling pathway
Schwitalla, Jan Claudius; Pakusch, Johanna; Mücher, Brix; Brückner, Alexander; Depke, Dominic Alexej; Fenzl, Thomas; De Zeeuw, Chris I; Kros, Lieke; Hoebeek, Freek E; Mark, Melanie D
(2022) Cellular and Molecular Life Sciences, volume 79, issue 4
(Article)
Abstract
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
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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.
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Keywords: Absence epilepsy, Chemogenetic stimulation, GPCR, Optogenetic stimulation, mGluR1, Molecular Medicine, Molecular Biology, Pharmacology, Cellular and Molecular Neuroscience, Cell Biology
ISSN: 1420-682X
Publisher: Birkhauser Verlag Basel
Note: Funding Information: Open Access funding enabled and organized by Projekt DEAL. JCS was supported by the Ruhr-University Bochum. This work was supported by DFG (German Research Foundation), SFB 1280 (Project number 316803389, Project A21; MDM), MA 5806/2-1 (MDM) and MA 5806/1-2 (MDM) and Netherlands Organization for Scientific Research (NWO-ALW 824.02.001; CIDZ), the Dutch Organization for Medical Sciences (ZonMW 91120067; CIDZ), Medical Neuro-Delta (MD 01092019-31082023; LK, CIDZ), INTENSE LSH-NWO (TTW/00798883; LK, CIDZ), ERC-adv (GA-294775 CIDZ), ERC-POC (nrs. 737619 and 768914; CIDZ), Veni (NWO-ZonMw, 91619109; LK) and Erasmus MC fellowship (LK). Publisher Copyright: © 2022, The Author(s).
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