@article{19794,
  abstract     = {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.},
  author       = {Currin, Christopher and Burman, Richard J. and Fedele, Tommaso and Ramantani, Georgia and Rosch, Richard E. and Sprekeler, Henning and Raimondo, Joseph V.},
  issn         = {1095-953X},
  journal      = {Neurobiology of Disease},
  publisher    = {Elsevier},
  title        = {{Network models incorporating chloride dynamics predict optimal strategies for terminating status epilepticus}},
  doi          = {10.1016/j.nbd.2025.106966},
  volume       = {212},
  year         = {2025},
}