CK2 Inhibition Prior to Status Epilepticus Persistently Enhances KCa2 Function in CA1 Which Slows Down Disease Progression

Felix Schulze; Steffen Müller; Xiati Guli; Lukas Schumann; Hannes Brehme; Till Riffert; Marco Rohde; Doreen Goerss; Simone Rackow; Anne Einsle; Timo Kirschstein; Rüdiger Köhling

doi:10.3389/fncel.2020.00033

CK2 Inhibition Prior to Status Epilepticus Persistently Enhances K_Ca2 Function in CA1 Which Slows Down Disease Progression

Front Cell Neurosci. 2020 Feb 26:14:33. doi: 10.3389/fncel.2020.00033. eCollection 2020.

Authors

Felix Schulze¹, Steffen Müller¹, Xiati Guli¹, Lukas Schumann¹, Hannes Brehme¹, Till Riffert¹, Marco Rohde¹, Doreen Goerss^{2

3}, Simone Rackow¹, Anne Einsle¹, Timo Kirschstein^{1

4}, Rüdiger Köhling^{1

4}

Affiliations

¹ Oscar Langendorff Institute of Physiology, University of Rostock, Rostock, Germany.
² Department of Psychosomatic Medicine, Rostock University Medical Center, Rostock, Germany.
³ German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany.
⁴ Center of Transdisciplinary Neurosciences Rostock, University of Rostock, Rostock, Germany.

Abstract

Purpose: Epilepsy therapy is currently based on anti-seizure drugs that do not modify the course of the disease, i.e., they are not anti-epileptogenic in nature. Previously, we observed that in vivo casein kinase 2 (CK2) inhibition with 4,5,6,7-tetrabromotriazole (TBB) had anti-epileptogenic effects in the acute epilepsy slice model.

Methods: Here, we pretreated rats with TBB in vivo prior to the establishment of a pilocarpine-induced status epilepticus (SE) in order to analyze the long-term sequelae of such a preventive TBB administration.

Results: We found that TBB pretreatment delayed onset of seizures after pilocarpine and slowed down disease progression during epileptogenesis. This was accompanied with a reduced proportion of burst firing neurons in the CA1 area. Western blot analyses demonstrated that CA1 tissue from TBB-pretreated epileptic animals contained significantly less CK2 than TBB-pretreated controls. On the transcriptional level, TBB pretreatment led to differential gene expression changes of K_Ca2.2, but also of HCN1 and HCN3 channels. Thus, in the presence of the HCN channel blocker ZD7288, pretreatment with TBB rescued the afterhyperpolarizing potential (AHP) as well as spike frequency adaptation in epileptic animals, both of which are prominent functions of K_Ca2 channels.

Conclusion: These data indicate that TBB pretreatment prior to SE slows down disease progression during epileptogenesis involving increased K_Ca2 function, probably due to a persistently decreased CK2 protein expression.

Keywords: Timm stain; field potential recording; intracellular recording; patch-clamp; temporal lobe epilepsy; video-EEG monitoring.