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 GABA A 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.
eEF2K/eEF2 Pathway Controls the Excitation/Inhibition Balance and Susceptibility to Epileptic Seizures / C. Heise, E. Taha, L. Murru, A. Cattaneo, F.C. Guarnieri, C. Montani, A. Mossa, E. Vezzoli, G. Ippolito, J. Zapata, I. Barrera, A.G. Ryazanov, J. Cook, M. Poe, M.R. Stephen, M. Kopanitsa, R. Benfante, F. Rusconi, D. Braida, M. Francolini, C.G. Proud, F. Valtorta, M. Passafaro, A. Bachi, C. Verpelli, K. Rosenblum, C. Sala, L. Ponzoni, M. Sala. - In: CEREBRAL CORTEX. - ISSN 1047-3211. - 27:3(2017 Mar), pp. 2226-2248.
|Titolo:||eEF2K/eEF2 Pathway Controls the Excitation/Inhibition Balance and Susceptibility to Epileptic Seizures|
|Parole Chiave:||Epilepsy; Fear conditioning; GABA receptors; Hippocampus; Inhibitory synapses; Translation elongation regulation; 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|
|Settore Scientifico Disciplinare:||Settore BIO/13 - Biologia Applicata|
|Data di pubblicazione:||mar-2017|
|Data ahead of print / Data di stampa:||2016|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1093/cercor/bhw075|
|Appare nelle tipologie:||01 - Articolo su periodico|