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

2016; Oxford University Press; Linguagem: Inglês

10.1093/cercor/bhw075

1460-2199

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

Genetics and Neurodevelopmental Disorders

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.