Role of chloride concentration in modulating seizure transitions in excitatory and inhibitory networks.

Abstract

Experimental evidence indicates that intracellular chloride concentration regulates the excitation-inhibition (EI) balance, yet the mechanisms by which activity-dependent chloride dynamics drive seizure evolution and stage transitions remain unclear. We present a conductance-based neuronal network in which EI balance emerges from chloride homeostasis via channel-mediated influx and transporter-mediated extrusion. We show that the fraction of inhibitory synaptic conductance contributing to channel-mediated influx acts as a control parameter that organizes seizure dynamics into distinct stages-preictal, ictal-tonic, and ictal-clonic-distinguished by characteristic amplitude and frequency signatures. Decreasing this fraction shortens ictal activity and suppresses seizure initiation, whereas high fraction promotes the emergence of ictal-tonic and ictal-clonic stages and spiral-wave dynamics, rendering seizure dynamics largely insensitive to inhibition. At intermediate values, seizures bypass the ictal-tonic stage and emerge directly as the ictal-clonic stage. Moreover, joint variation of fractions with synaptic strengths reveals that recurrent excitation expands the tonic-clonic seizure, while recurrent inhibition prolongs preictal states and suppresses ictal-clonic activity.