GSK3β activity alleviates epileptogenesis and limits GluA1 phosphorylation

Malgorzata Urbanska, Paulina Kazmierska-Grebowska, Tomasz Kowalczyk, Bartosz Caban, Karolina Nader, Barbara Pijet, Katarzyna Kalita, Agata Gozdz, Herman Devijver, Benoit Lechat, Tomasz Jaworski, Wieslawa Grajkowska, Krzysztof Sadowski, Sergiusz Jozwiak, Katarzyna Kotulska, Jan Konopacki, Fred van Leuven, Erwin A. van Vliet, Eleonora Aronica, Jacek Jaworski

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Background: Glycogen synthase kinase-3β (GSK3β) is a key regulator of cellular homeostasis. In neurons, GSK3β contributes to the control of neuronal transmission and plasticity, but its role in epilepsy remains to be defined. Methods: Biochemical and electrophysiological methods were used to assess the role of GSK3β in regulating neuronal transmission and epileptogenesis. GSK3β activity was increased genetically in GSK3β[S9A] mice. Its effects on neuronal transmission and epileptogenesis induced by kainic acid were assessed by field potential recordings in mice brain slices and video electroencephalography in vivo. The ion channel expression was measured in brain samples from mice and followed by analysis in samples from patients with temporal lobe epilepsy or focal cortical dysplasia in correlation to GSK3β phosphorylation. Findings: Higher GSK3β activity decreased the progression of kainic acid induced epileptogenesis. At the biochemical level, higher GSK3β activity increased the expression of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel 4 under basal conditions and in the epileptic mouse brain and decreased phosphorylation of the glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluA1 at Serine 831 under basal conditions. Moreover, we found a significant correlation between higher inhibitory GSK3β phosphorylation at Serine 9 and higher activating GluA1 phosphorylation at Serine 845 in brain samples from epileptic patients. Interpretation: Our data imply GSK3β activity in the protection of neuronal networks from hyper-activation in response to epileptogenic stimuli and indicate that the anti-epileptogenic function of GSK3β involves modulation of HCN4 level and the synaptic AMPA receptors pool.
Original languageEnglish
Pages (from-to)377-387
Number of pages11
JournalEBioMedicine
Volume39
Early online date2018
DOIs
Publication statusPublished - 1 Jan 2019
Externally publishedYes

Cite this

Urbanska, M., Kazmierska-Grebowska, P., Kowalczyk, T., Caban, B., Nader, K., Pijet, B., ... Jaworski, J. (2019). GSK3β activity alleviates epileptogenesis and limits GluA1 phosphorylation. EBioMedicine, 39, 377-387. https://doi.org/10.1016/j.ebiom.2018.11.040