eEF2K/eEF2 Pathway Controls the Excitation/Inhibition Balance and Susceptibility to Epileptic Seizures

Christopher Heise, Elham Taha, Luca Murru, Luisa Ponzoni, Angela Cattaneo, Fabrizia C Guarnieri, Caterina Montani, Adele Mossa, Elena Vezzoli, Giulio Ippolito, Jonathan Zapata, Iliana Barrera, Alexey G Ryazanov, James Cook, Michael Poe, Michael Rajesh Stephen, Maksym Kopanitsa, Roberta Benfante, Francesco Rusconi, Daniela BraidaMaura Francolini, Christopher G Proud, Flavia Valtorta, Maria Passafaro, Mariaelvina Sala, Angela Bachi, Chiara Verpelli, Kobi Rosenblum, Carlo Sala

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Alterations in the balance of inhibitory and excitatory synaptic transmission have been implicated in the pathogenesis of neurological disorders such as epilepsy. Eukaryotic elongation factor 2 kinase (eEF2K) is a highly regulated, ubiquitous kinase involved in the control of protein translation. Here, we show that eEF2K activity negatively regulates GABAergic synaptic transmission. Indeed, loss of eEF2K increases GABAergic synaptic transmission by upregulating the presynaptic protein Synapsin 2b and α5-containing GABAA receptors and thus interferes with the excitation/inhibition balance. This cellular phenotype is accompanied by an increased resistance to epilepsy and an impairment of only a specific hippocampal-dependent fear conditioning. From a clinical perspective, our results identify eEF2K as a potential novel target for antiepileptic drugs, since pharmacological and genetic inhibition of eEF2K can revert the epileptic phenotype in a mouse model of human epilepsy.

Original languageEnglish
Pages (from-to)2226-2248
Number of pages23
JournalCerebral Cortex
Volume27
Issue number3
DOIs
Publication statusPublished - 1 Mar 2017
Externally publishedYes

Keywords

  • Animals
  • Cells, Cultured
  • Cerebral Cortex
  • Conditioning (Psychology)
  • Disease Models, Animal
  • Elongation Factor 2 Kinase
  • Epilepsy
  • Fear
  • Hippocampus
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neural Inhibition
  • Neurons
  • Rats, Sprague-Dawley
  • Receptors, GABA-A
  • Synapsins
  • Synaptic Transmission
  • gamma-Aminobutyric Acid
  • Journal Article

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Heise, C., Taha, E., Murru, L., Ponzoni, L., Cattaneo, A., Guarnieri, F. C., ... Sala, C. (2017). eEF2K/eEF2 Pathway Controls the Excitation/Inhibition Balance and Susceptibility to Epileptic Seizures. Cerebral Cortex, 27(3), 2226-2248. https://doi.org/10.1093/cercor/bhw075