Network models incorporating chloride dynamics predict optimal strategies for terminating status epilepticus.

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.