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Irregular RNA splicing curtails postsynaptic gephyrin in the cornu ammonis of patients with epilepsy

Item Type:Article
Title:Irregular RNA splicing curtails postsynaptic gephyrin in the cornu ammonis of patients with epilepsy
Creators Name:Foerstera, B. and Belaidi, A.A. and Juettner, R. and Bernert, C. and Tsokos, M. and Lehmann, T.N. and Horn, P. and Dehnicke, C. and Schwarz, G. and Meier, J.C.
Abstract:Anomalous hippocampal inhibition is involved in temporal lobe epilepsy, and reduced gephyrin immunoreactivity in the temporal lobe epilepsy hippocampus has been reported recently. However, the mechanisms responsible for curtailing postsynaptic gephyrin scaffolds are poorly understood. Here, we have investigated gephyrin expression in the hippocampus of patients with intractable temporal lobe epilepsy. Immunohistochemical and western blot analyses revealed irregular gephyrin expression in the cornu ammonis of patients with temporal lobe epilepsy and four abnormally spliced gephyrins lacking several exons in their G-domains were isolated. Identified temporal lobe epilepsy gephyrins have oligomerization deficits and they curtail hippocampal postsynaptic gephyrin and GABA(A) receptor α2 while interacting with regularly spliced gephyrins. We found that cellular stress (alkalosis and hyperthermia) induces exon skipping in gephyrin messenger RNA, which is responsible for curtailed postsynaptic gephyrin and GABA(A) receptor α2 scaffolds. Accordingly, we did not obtain evidence for gephyrin gene mutations in patients with temporal lobe epilepsy. Cellular stress such as alkalosis, for example arising from seizure activity, could thus facilitate the development of temporal lobe epilepsy by reducing GABA(A) receptor α2-mediated hippocampal synaptic transmission selectively in the cornu ammonis.
Keywords:Epilepsy, Hippocampus, Gephyrin, GABA(A) Receptor, RNA Splicing, Exon Skipping, Cellular Stress, Molybdenum Cofactor, Animals, Rats
Publisher:Oxford University Press
Page Range:3778-3794
Date:December 2010
Official Publication:https://doi.org/10.1093/brain/awq298
PubMed:View item in PubMed

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