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 journalArticlepeer-review

53 Citations (Scopus)


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 hippocampaldependent 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
Issue number3
Publication statusPublished or Issued - 2017
Externally publishedYes


  • Epilepsy
  • Fear conditioning
  • GABA receptors
  • Hippocampus
  • Inhibitory synapses
  • Translation elongation regulation

ASJC Scopus subject areas

  • Cognitive Neuroscience
  • Cellular and Molecular Neuroscience

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