Collapse of feed-forward inhibition underpins hyperexcitability in GABAA receptor gain-of-function epilepsy.
Overview
- The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria 3010, Australia
- Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark
- Brain and Mind Centre, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales 2006, Australia
- Department of Neurology, Eastern Health, Victoria 3128, Australia
- Centre for Eye Research Australia, University of Melbourne, Victoria 3002, Australia
- Life Sciences Center, Vilnius University, Vilnius LT-10257, Lithuania
- School of Science, University of Western Sydney, Sydney, New South Wales 2751, Australia
- Department of Epilepsy, Genetics and Personalized Medicine, Member of ERN, EpiCare, Danish Epilepsy Centre, Dianalund DK-4293, Denmark
- Department of Regional Health Research, Faculty of Health Sciences, University of Southern Denmark, Odense DK-5230, Denmark
Abstract
Gain-of-function (GOF) variants in γ-aminobutyric acid type A (GABAA) receptors are increasingly recognized as a cause of severe developmental and epileptic encephalopathies. However, the mechanisms by which enhanced GABAA receptor activity leads to neuronal network hyperexcitability remain unclear. We engineered a new mouse model based on the human GOF GABRB3 p.(Glu77Lys) variant (β3E77K), identified in two individuals diagnosed with developmental and epileptic encephalopathies, to explore the mechanisms underlying GABAA receptor GOF disease. The phenotypes of β3E77K mice included embryonic lethality consistent with a severe early developmental impact of the GOF GABAA receptor variant. These mice display spike-wave-like discharges that were exacerbated by vigabatrin and ameliorated by valproate, matching the clinical observations of GOF GABRB3 patients. β3E77K mice also have increased proconvulsant-induced seizure susceptibility and a broad increase in electrocorticographic spectral power amplitude, indicative of cortical hyperexcitability. Additionally, neurological assessments revealed hypoactivity and weakened grip strength.
Ex vivo electrophysiological recordings demonstrated increased GABAA receptor-mediated current amplitudes at both excitatory and inhibitory synapses in CA1 hippocampus, consistent with the GOF molecular phenotype previously identified in functional studies. In cortical layer 2/
Our findings highlight the critical role of interneuron network dysfunction in driving cortical hyperexcitability caused by GOF GABAA receptor variants. They provide a novel pathogenic mechanism in developmental and epileptic encephalopathies that could have broader implications for disorders involving dysfunction in GABAergic neurons. The β3E77K mouse also provides a unique preclinical model to test therapeutic strategies in GOF GABAA receptor disease.
Reproduced under the paper's license (CC BY), from the paper cited above.
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Data
Datasets cited
- portal.brain-map.org/
atlases-and-data/ , at Allen Brain Map; found in the text, “RNA-sequencing dataset”rnaseq
Data availability
Raw data and images are available upon request from the corresponding author.
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.
Version 1, 4 November 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 23 authors, 6 keywords, 11 MeSH terms, 5 funders, 0 references.
Cite
This paper
McKenzie, C. E., Aung, K. P., Dos Santos, A. B., Mao, M., Spyrou, J., Bryson, A., Wong, R., Lin, S. X. N., Bleakley, L. E., Palmqvist, J., Guzulaitis, R., Kan, A. S. H., Liao, V. W. Y., Soh, M. S., Gomez, C. D., Larsen, V., Petersen, A. M. N., Absalom, N. L., Møller, R. S., . . . Reid, C. A. (2026). Collapse of feed-forward inhibition underpins hyperexcitability in GABAA receptor gain-of-function epilepsy. Brain : a journal of neurology, 149(11), 3789-3805. https://
BibTeX
@article{mckenzie2026col
author = {McKenzie, Chaseley E and Aung, Khaing Phyu and Dos Santos, Altair Brito and Mao, Miaomiao and Spyrou, James and Bryson, Alexander and Wong, Raymond and Lin, Susan X N and Bleakley, Lauren E and Palmqvist, Joakim and Guzulaitis, Robertas and Kan, Anthony S H and Liao, Vivian W Y and Soh, Ming S and Gomez, Carlos Daniel and Larsen, Victor and Petersen, Anne Marie Nordvig and Absalom, Nathan L and Møller, Rikke S and Chebib, Mary and Perrier, Jean-François and Ahring, Philip K and Reid, Christopher A},
title = {{Collapse of feed-forward inhibition underpins hyperexcitability in GABAA receptor gain-of-function epilepsy}},
journal = {Brain : a journal of neurology},
year = {2026},
month = nov,
volume = {149},
number = {11},
pages = {3789--3805},
publisher = {Oxford University Press},
issn = {0006-8950},
doi = {10.1093/
url = {https://
pmid = {42017314},
pmcid = {PMC13730555}
}
RIS
TY - JOUR
AU - McKenzie, Chaseley E
AU - Aung, Khaing Phyu
AU - Dos Santos, Altair Brito
AU - Mao, Miaomiao
AU - Spyrou, James
AU - Bryson, Alexander
AU - Wong, Raymond
AU - Lin, Susan X N
AU - Bleakley, Lauren E
AU - Palmqvist, Joakim
AU - Guzulaitis, Robertas
AU - Kan, Anthony S H
AU - Liao, Vivian W Y
AU - Soh, Ming S
AU - Gomez, Carlos Daniel
AU - Larsen, Victor
AU - Petersen, Anne Marie Nordvig
AU - Absalom, Nathan L
AU - Møller, Rikke S
AU - Chebib, Mary
AU - Perrier, Jean-François
AU - Ahring, Philip K
AU - Reid, Christopher A
TI - Collapse of feed-forward inhibition underpins hyperexcitability in GABAA receptor gain-of-function epilepsy
T2 - Brain : a journal of neurology
J2 - Brain
PY - 2026
DA - 2026/
VL - 149
IS - 11
SP - 3789
EP - 3805
SN - 0006-8950
PB - Oxford University Press
DO - 10.1093/
UR - https://
LA - en
ER -
CSL-JSON
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