---
DOAJ_listed: '1'
OA_place: publisher
OA_type: gold
_id: '19794'
abstract:
- lang: eng
text: Status epilepticus (SE), seizures lasting beyond five minutes, is a medical
emergency commonly treated with benzodiazepines which enhance GABAA receptor (GABAAR)
conductance. Despite widespread use, benzodiazepines fail in over one-third of
patients, potentially due to seizure-induced disruption of neuronal chloride (Cl−)
homeostasis. Understanding these changes at a network level is crucial for improving
clinical translation. Here, we address this using a large-scale spiking neural
network model incorporating Cl− dynamics, informed by clinical EEG and experimental
slice recordings. Our simulations confirm that the GABAAR reversal potential (EGABA)
dictates the pro- or anti-seizure effect of GABAAR conductance modulation, with
high EGABA rendering benzodiazepines ineffective or excitatory. We show SE-like
activity and EGABA depend non-linearly on Cl− extrusion efficacy and GABAAR conductance.
Critically, cell-type specific manipulations reveal that pyramidal cell, not interneuron,
Cl− extrusion predominantly determines the severity of SE activity and the response
to simulated benzodiazepines. Leveraging these mechanistic insights, we develop
a predictive framework mapping network states to Cl− extrusion capacity and GABAergic
load, yielding a proposed decision-making strategy to guide therapeutic interventions
based on initial treatment response. This work identifies pyramidal cell Cl− handling
as a key therapeutic target and demonstrates the utility of biophysically detailed
network models for optimising SE treatment protocols.
acknowledgement: 'The research leading to these results has received support from
the National Research Foundation of South Africa, the Deutscher Akademischer Austauschdienst,
NOMIS Foundation, NVIDIA Academic Program, the University of Cape Town, the Anna
Mueller Grocholski Foundation, the Swiss National Science Foundation (SNSF: 208184),
the Gabriel Foundation, a Wellcome Trust Seed Award (214042/Z/18/Z), the South African
Medical Research Council and the FLAIR Fellowship Programme (FLR\R1\190829): a partnership
between the African Academy of Sciences and the Royal Society funded by the UK Government''s
Global Challenges Research Fund and a Wellcome Trust International Intermediate
Fellowship (222968/Z/21/Z).'
article_number: '106966'
article_processing_charge: Yes
article_type: original
author:
- first_name: Christopher
full_name: Currin, Christopher
id: e8321fc5-3091-11eb-8a53-83f309a11ac9
last_name: Currin
orcid: 0000-0002-4809-5059
- first_name: Richard J.
full_name: Burman, Richard J.
last_name: Burman
- first_name: Tommaso
full_name: Fedele, Tommaso
last_name: Fedele
- first_name: Georgia
full_name: Ramantani, Georgia
last_name: Ramantani
- first_name: Richard E.
full_name: Rosch, Richard E.
last_name: Rosch
- first_name: Henning
full_name: Sprekeler, Henning
last_name: Sprekeler
- first_name: Joseph V.
full_name: Raimondo, Joseph V.
last_name: Raimondo
citation:
ama: Currin C, Burman RJ, Fedele T, et al. Network models incorporating chloride
dynamics predict optimal strategies for terminating status epilepticus. Neurobiology
of Disease. 2025;212. doi:10.1016/j.nbd.2025.106966
apa: Currin, C., Burman, R. J., Fedele, T., Ramantani, G., Rosch, R. E., Sprekeler,
H., & Raimondo, J. V. (2025). Network models incorporating chloride dynamics
predict optimal strategies for terminating status epilepticus. Neurobiology
of Disease. Elsevier. https://doi.org/10.1016/j.nbd.2025.106966
chicago: Currin, Christopher, Richard J. Burman, Tommaso Fedele, Georgia Ramantani,
Richard E. Rosch, Henning Sprekeler, and Joseph V. Raimondo. “Network Models Incorporating
Chloride Dynamics Predict Optimal Strategies for Terminating Status Epilepticus.”
Neurobiology of Disease. Elsevier, 2025. https://doi.org/10.1016/j.nbd.2025.106966.
ieee: C. Currin et al., “Network models incorporating chloride dynamics predict
optimal strategies for terminating status epilepticus,” Neurobiology of Disease,
vol. 212. Elsevier, 2025.
ista: Currin C, Burman RJ, Fedele T, Ramantani G, Rosch RE, Sprekeler H, Raimondo
JV. 2025. Network models incorporating chloride dynamics predict optimal strategies
for terminating status epilepticus. Neurobiology of Disease. 212, 106966.
mla: Currin, Christopher, et al. “Network Models Incorporating Chloride Dynamics
Predict Optimal Strategies for Terminating Status Epilepticus.” Neurobiology
of Disease, vol. 212, 106966, Elsevier, 2025, doi:10.1016/j.nbd.2025.106966.
short: C. Currin, R.J. Burman, T. Fedele, G. Ramantani, R.E. Rosch, H. Sprekeler,
J.V. Raimondo, Neurobiology of Disease 212 (2025).
corr_author: '1'
date_created: 2025-06-08T22:01:22Z
date_published: 2025-08-01T00:00:00Z
date_updated: 2025-12-30T08:36:36Z
day: '01'
ddc:
- '570'
department:
- _id: TiVo
doi: 10.1016/j.nbd.2025.106966
external_id:
isi:
- '001501576500001'
file:
- access_level: open_access
checksum: abe215be676ed14e9a37fb78b6a5a610
content_type: application/pdf
creator: dernst
date_created: 2025-12-30T08:35:41Z
date_updated: 2025-12-30T08:35:41Z
file_id: '20896'
file_name: 2025_NeurobioDisease_Currin.pdf
file_size: 7063352
relation: main_file
success: 1
file_date_updated: 2025-12-30T08:35:41Z
fulldoi: https://doi.org/10.1016/j.nbd.2025.106966
has_accepted_license: '1'
intvolume: ' 212'
isi: 1
language:
- iso: eng
license: https://creativecommons.org/licenses/by-nc/4.0/
month: '08'
oa: 1
oa_version: Published Version
publication: Neurobiology of Disease
publication_identifier:
eissn:
- 1095-953X
issn:
- 0969-9961
publication_status: published
publisher: Elsevier
quality_controlled: '1'
scopus_import: '1'
status: public
title: Network models incorporating chloride dynamics predict optimal strategies for
terminating status epilepticus
tmp:
image: /images/cc_by_nc.png
legal_code_url: https://creativecommons.org/licenses/by-nc/4.0/legalcode
name: Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)
short: CC BY-NC (4.0)
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 212
year: '2025'
...