eEF2K/eEF2 Pathway Controls the Excitation/Inhibition Balance and Susceptibility to Epileptic Seizures
Open accessAbstract
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.
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eEF2K inhibition extends plasticity without driving excitotoxicity.
“eEF2K inhibition offers a distinctive advantage by extending plasticity without driving excitotoxicity [152,153,154].”
From Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery (2026) · cites this paper as [153]
The Introduction reports that eEF2K knockout mice were less susceptible to seizures, and that genetic or pharmacological inhibition rescued an epileptic phenotype in a mouse model. But the section on excitatory and inhibitory synapses reports normal long-term potentiation in knockout mice, not extended plasticity. The paper does not establish that inhibition avoids excitotoxicity; reduced seizure susceptibility is a narrower finding. (LLM, conf=0.86)
Experimental — accuracy not yet measuredeEF2K inhibition's calibrated potentiation supports learning-related plasticity while preserving network stability.
“This calibrated potentiation supports learning related plasticity while preserving network stability [152,153,154].”
From Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery (2026) · cites this paper as [153]
The Introduction and the section on seizure susceptibility report stronger inhibitory transmission and reduced seizure susceptibility after eEF2K loss, supporting the network-stability aspect. But the synaptic-balance section reports normal, not enhanced, hippocampal LTP, and the paper reports a specific hippocampal memory impairment. It does not establish that eEF2K inhibition supports learning-related plasticity while preserving stability. (LLM, conf=0.86)
Experimental — accuracy not yet measuredeEF2K inhibition strengthens inhibitory tone and increases seizure resistance, indicating a favorable excitation-inhibition balance.
“Strengthening of inhibitory tone and increased seizure resistance further indicate a favorable excitation inhibition balance [153,155].”
From Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery (2026) · cites this paper as [153]
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- Authors
- 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., Braida, D., Francolini, M., Proud, C. G., Valtorta, F., Passafaro, M., Sala, M., Bachi, A., Verpelli, C., Rosenblum, K., & Sala, C.
- Affiliations
- University of Haifa (IL)
- University of Milan (IT)
- IFOM (IT)
- Vita-Salute San Raffaele University (IT)
- University of Medicine and Dentistry of New Jersey (US)
- University of Wisconsin–Milwaukee (US)
- Synome (United Kingdom) (GB)
- South Australian Health and Medical Research Institute (AU)
- Corresponding author
- Sala, Carlo
- ORCID
- Murru, Luca
- Ponzoni, Luisa
- Guarnieri, Fabrizia C.
- Montani, Caterina
- Mossa, Adele
- Vezzoli, Elena
- Zapata, Jonathan
- 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
- Venue
- Cerebral Cortex
- Publisher
- Oxford University Press (OUP)
- Published
- 2016-03-21
- Volume
- 27
- Issue
- 3
- Pages
- bhw075
- ISSN
- 1047-3211 (ISSN-L)
- 1460-2199
- PMC
- PMC5963824
- OpenAlex
- W2306974599
- Cited by
- 62
- References
- 11
- Citations by year
- 2025: 1 · 2024: 5 · 2023: 4 · 2022: 8 · 2021: 7 · 2020: 14 · 2019: 7 · 2018: 6 · 2017: 6 · 2016: 4
- FWCI
- 6.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cerebral Cortex (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
- Funders
- Comitato Telethon Fondazione Onlus (GGP13187)
- Fondazione CARIPLO
- Italian Institute of Technology
- Ministry of Health
- ERA-NET NEURON
- Italian Ministry for Research
- SyMBaD
- German-Israeli Foundation (RO3971/1-1)
- Israel Science Foundation (1003/12)
- Israeli Planning and Budgeting Committee
- Ministry of Science and Technology
- Israel Society for Neuroscience
- Wellcome Trust (086688, 1R01 MH096463-01A1, 1R01 NSW076517-01A1)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- eEF2K, elongation factor 2, excitation-inhibition balance, GABAergic neurotransmission, epileptic seizures, epilepsy susceptibility, antiepileptic drug targets, translational regulation
- MeSH terms
- Animals, Cells, Cultured, Cerebral Cortex, Conditioning, Psychological, Disease Models, Animal, Epilepsy, Fear, gamma-Aminobutyric Acid, Hippocampus, Mice, Inbred C57BL, Neural Inhibition, Synaptic Transmission, Neurons, Receptors, GABA-A, Synapsins, Rats, Sprague-Dawley, Mice, Knockout, Elongation Factor 2 Kinase
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