title: eEF2K/eEF2 Pathway Controls the Excitation/Inhibition Balance and Susceptibility to Epileptic Seizures.
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.
authors.affiliation: CNR Neuroscience Institute, Milan, Italy.
authors.forename: Christopher
authors.initials: C
authors.lastname: Heise
authors.affiliation: Sagol Department of Neurobiology, University of Haifa, Haifa, Israel.|Center for Gene Manipulation in the Brain, Natural Science Faculty, University of Haifa, Haifa, Israel.
authors.forename: Elham
authors.initials: E
authors.lastname: Taha
authors.affiliation: CNR Neuroscience Institute, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Murru
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Ponzoni
authors.affiliation: IFOM-FIRC Institute of Molecular Oncology, Milan, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Cattaneo
authors.affiliation: Division of Neuroscience, San Raffaele Scientific Institute and Vita-Salute University, Milan, Italy.
authors.forename: Fabrizia C
authors.initials: FC
authors.lastname: Guarnieri
authors.affiliation: CNR Neuroscience Institute, Milan, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Montani
authors.affiliation: CNR Neuroscience Institute, Milan, Italy.
authors.forename: Adele
authors.initials: A
authors.lastname: Mossa
authors.affiliation: CNR Neuroscience Institute, Milan, Italy.|Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Vezzoli
authors.affiliation: CNR Neuroscience Institute, Milan, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Ippolito
authors.affiliation: CNR Neuroscience Institute, Milan, Italy.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Zapata
authors.affiliation: Sagol Department of Neurobiology and.|Center for Gene Manipulation in the Brain, Natural Science Faculty, University of Haifa, Haifa, Israel.
authors.forename: Iliana
authors.initials: I
authors.lastname: Barrera
authors.affiliation: The Department of Pharmacology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
authors.forename: Alexey G
authors.initials: AG
authors.lastname: Ryazanov
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.
authors.forename: James
authors.initials: J
authors.lastname: Cook
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Poe
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.
authors.forename: Michael Rajesh
authors.initials: MR
authors.lastname: Stephen
authors.affiliation: Synome, Babraham Research Campus, Cambridge CB22 3AT, UK.|Charles River Discovery Research Services, 70210 Kuopio, Finland.
authors.forename: Maksym
authors.initials: M
authors.lastname: Kopanitsa
authors.affiliation: CNR Neuroscience Institute, Milan, Italy.|Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Benfante
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Rusconi
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Braida
authors.affiliation: CNR Neuroscience Institute, Milan, Italy.|Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy.
authors.forename: Maura
authors.initials: M
authors.lastname: Francolini
authors.affiliation: University of Southampton, Centre for Biological Sciences, Southampton SO17 1BJ, UK.|South Australian Health and Medical Research Institute and University of Adelaide, Adelaide, Australia.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Proud
authors.affiliation: Division of Neuroscience, San Raffaele Scientific Institute and Vita-Salute University, Milan, Italy.
authors.forename: Flavia
authors.initials: F
authors.lastname: Valtorta
authors.affiliation: CNR Neuroscience Institute, Milan, Italy.|Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Passafaro
authors.affiliation: CNR Neuroscience Institute, Milan, Italy.|Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy.
authors.forename: Mariaelvina
authors.initials: M
authors.lastname: Sala
authors.affiliation: IFOM-FIRC Institute of Molecular Oncology, Milan, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Bachi
authors.affiliation: CNR Neuroscience Institute, Milan, Italy.|Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Verpelli
authors.affiliation: Sagol Department of Neurobiology and.|Center for Gene Manipulation in the Brain, Natural Science Faculty, University of Haifa, Haifa, Israel.
authors.forename: Kobi
authors.initials: K
authors.lastname: Rosenblum
authors.affiliation: CNR Neuroscience Institute, Milan, Italy, Università degli Studi di Milano, Milan, Italy.|Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Sala
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D003213:Conditioning, Psychological / Q000502:physiology; D004195:Disease Models, Animal; D054736:Elongation Factor 2 Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004827:Epilepsy / Q000201:enzymology* / Q000473:pathology; D005239:Fear / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism; D016704:Synapsins / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: C496250:Gabra5 protein, mouse; D011963:Receptors, GABA-A; D016704:Synapsins; D005680:gamma-Aminobutyric Acid; C517691:Eef2k protein, rat; C517690:Eef2k protein, mouse; D054736:Elongation Factor 2 Kinase
keywords: GABA receptors; epilepsy; fear conditioning; hippocampus; inhibitory synapses; translation elongation regulation