Authors: Urbanska M., Kazmierska-Grebowska P., Kowalczyk T., Caban B., Nader K., Pijet B., Kalita K., Gozdz A., Devijver H., Lechat B., Jaworski T., Grajkowska W., Sadowski K., Jozwiak S., Kotulska K., Konopacki J., Van Leuven F., van Vliet E.A., Aronica E., Jaworski J.
Ebiomedicine 39 (2019), 377-387
Background: Glycogen synthase kinase-3beta (GSK3B) is a key regulator of cellular homeostasis. In neurons, GSK3B 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 GSK3B in regulating neuronal transmission and epileptogenesis. GSK3B activity was increased genetically in GSK3B(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 GSK3B phosphorylation.
Findings: Higher GSK3B activity decreased the progression of kainic acid induced epileptogenesis. At the biochemical level, higher GSK3B 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 alpha-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 GSK3B phorphorylation at Serine 9 and higher activitating GluA1 phosphorylation at Serine 845 in brain samples from epileptic patients.
Interpretation: Our data imply GSK3B activity in the protection of neuronal networks from hyper-activation in response to epileptogenic stimuli and indicate that the anti-epileptogenic function of GSK3B involves modulation of HCN4 level and the synaptic AMPA receptors pool.