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 Ryazanov, James Cook, Michael Poe, Michael Rajesh Stephen, Maksym Kopanitsa, Roberta Benfante, Francesco Rusconi, Daniela Braida & 9 others Maura Francolini, Christopher G. Proud, Flavia Valtorta, Maria Passafaro, Mariaelvina Sala, Angela Bachi, Chiara Verpelli, Kobi Rosenblum, Carlo Sala

Research output: Contribution to journalArticle

18 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)2226-2248
Number of pages23
JournalCerebral Cortex
Volume27
Issue number3
DOIs
StatePublished - Jan 1 2017

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Elongation Factor 2 Kinase
Epilepsy
Synaptic Transmission
Synapsins
Phenotype
Protein Biosynthesis
GABA-A Receptors
Nervous System Diseases
Anticonvulsants
Fear
Phosphotransferases
Inhibition (Psychology)
Pharmacology

All Science Journal Classification (ASJC) codes

  • Cellular and Molecular Neuroscience
  • Cognitive Neuroscience

Cite this

Heise, C., Taha, E., Murru, L., Ponzoni, L., Cattaneo, A., Guarnieri, F. C., ... 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
Heise, Christopher ; Taha, Elham ; Murru, Luca ; Ponzoni, Luisa ; Cattaneo, Angela ; Guarnieri, Fabrizia C. ; Montani, Caterina ; Mossa, Adele ; Vezzoli, Elena ; Ippolito, Giulio ; Zapata, Jonathan ; Barrera, Iliana ; Ryazanov, Alexey ; Cook, James ; Poe, Michael ; Stephen, Michael Rajesh ; Kopanitsa, Maksym ; Benfante, Roberta ; Rusconi, Francesco ; Braida, Daniela ; Francolini, Maura ; Proud, Christopher G. ; Valtorta, Flavia ; Passafaro, Maria ; Sala, Mariaelvina ; Bachi, Angela ; Verpelli, Chiara ; Rosenblum, Kobi ; Sala, Carlo. / EEF2K/eEF2 pathway controls the excitation/inhibition balance and susceptibility to epileptic seizures. In: Cerebral Cortex. 2017 ; Vol. 27, No. 3. pp. 2226-2248.
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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.",
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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, A, 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

EEF2K/eEF2 pathway controls the excitation/inhibition balance and susceptibility to epileptic seizures. / Heise, Christopher; Taha, Elham; Murru, Luca; Ponzoni, Luisa; Cattaneo, Angela; Guarnieri, Fabrizia C.; Montani, Caterina; Mossa, Adele; Vezzoli, Elena; Ippolito, Giulio; Zapata, Jonathan; Barrera, Iliana; Ryazanov, Alexey; Cook, James; Poe, Michael; Stephen, Michael Rajesh; Kopanitsa, Maksym; Benfante, Roberta; Rusconi, Francesco; Braida, Daniela; Francolini, Maura; Proud, Christopher G.; Valtorta, Flavia; Passafaro, Maria; Sala, Mariaelvina; Bachi, Angela; Verpelli, Chiara; Rosenblum, Kobi; Sala, Carlo.

In: Cerebral Cortex, Vol. 27, No. 3, 01.01.2017, p. 2226-2248.

Research output: Contribution to journalArticle

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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

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

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