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 Braida; Maura Francolini; Christopher G. Proud; Flavia Valtorta; Maria Passafaro; Mariaelvina Sala; Angela Bachi; Chiara Verpelli; Kobi Rosenblum; Carlo Sala

doi:https://doi.org/10.1093/cercor/bhw075

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

Department of Neurobiology

University of Haifa

Research output: Contribution to journal › Article › peer-review

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 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.

Original language	American English
Pages (from-to)	2226-2248
Number of pages	23
Journal	Cerebral Cortex
Volume	27
Issue number	3
DOIs	https://doi.org/10.1093/cercor/bhw075
State	Published - 2017

Keywords

Epilepsy
Fear conditioning
GABA receptors
Hippocampus
Inhibitory synapses
Translation elongation regulation

All Science Journal Classification (ASJC) codes

Cellular and Molecular Neuroscience
Cognitive Neuroscience

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Heise, C., Taha, E., Murru, L., Ponzoni, L., Cattaneo, A., Guarnieri, F. C., Montani, C., Mossa, A., Vezzoli, E., Ippolito, G., Zapata, J., Barrera, I., Ryazanov, A. G., Cook, J., Poe, M., Stephen, M. R., Kopanitsa, M., Benfante, R., Rusconi, F., ... 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

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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 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.",

keywords = "Epilepsy, Fear conditioning, GABA receptors, Hippocampus, Inhibitory synapses, Translation elongation regulation",

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

year = "2017",

doi = "https://doi.org/10.1093/cercor/bhw075",

language = "American English",

volume = "27",

pages = "2226--2248",

journal = "Cerebral Cortex",

issn = "1047-3211",

publisher = "Oxford University Press",

number = "3",

}

Heise, C, Taha, E, Murru, L, Ponzoni, L, Cattaneo, A, Guarnieri, FC, Montani, C, Mossa, A, Vezzoli, E, Ippolito, G, Zapata, J, Barrera, I, Ryazanov, AG, Cook, J, Poe, M, Stephen, MR, Kopanitsa, M, Benfante, R, Rusconi, F, Braida, D, Francolini, M, Proud, CG, Valtorta, F, Passafaro, M, Sala, M, Bachi, A, Verpelli, C, Rosenblum, K & Sala, C 2017, 'EEF2K/eEF2 pathway controls the excitation/inhibition balance and susceptibility to epileptic seizures', Cerebral Cortex, vol. 27, no. 3, pp. 2226-2248. https://doi.org/10.1093/cercor/bhw075

TY - JOUR

T1 - EEF2K/eEF2 pathway controls the excitation/inhibition balance and susceptibility to epileptic seizures

AU - Heise, Christopher

AU - Taha, Elham

AU - Murru, Luca

AU - Ponzoni, Luisa

AU - Cattaneo, Angela

AU - Guarnieri, Fabrizia C.

AU - Montani, Caterina

AU - Mossa, Adele

AU - Vezzoli, Elena

AU - Ippolito, Giulio

AU - Zapata, Jonathan

AU - Barrera, Iliana

AU - Ryazanov, Alexey G.

AU - Cook, James

AU - Poe, Michael

AU - Stephen, Michael Rajesh

AU - Kopanitsa, Maksym

AU - Benfante, Roberta

AU - Rusconi, Francesco

AU - Braida, Daniela

AU - Francolini, Maura

AU - Proud, Christopher G.

AU - Valtorta, Flavia

AU - Passafaro, Maria

AU - Sala, Mariaelvina

AU - Bachi, Angela

AU - Verpelli, Chiara

AU - Rosenblum, Kobi

AU - Sala, Carlo

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

KW - Epilepsy

KW - Fear conditioning

KW - GABA receptors

KW - Hippocampus

KW - Inhibitory synapses

KW - Translation elongation regulation

UR - http://www.scopus.com/inward/record.url?scp=85019769606&partnerID=8YFLogxK

U2 - https://doi.org/10.1093/cercor/bhw075

DO - https://doi.org/10.1093/cercor/bhw075

M3 - Article

C2 - 27005990

SN - 1047-3211

VL - 27

SP - 2226

EP - 2248

JO - Cerebral Cortex

JF - Cerebral Cortex

IS - 3

ER -

EEF2K/eEF2 pathway controls the excitation/inhibition balance and susceptibility to epileptic seizures

Abstract

Keywords

All Science Journal Classification (ASJC) codes

UN SDGs

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