Depolarizing Effect of Chloride Influx Through KCC and NKCC During Nonsynaptic Epileptiform Activity

Chloride accumulation inside neurons is related to excitability and to the induction and maintenance of epileptiform activity. Studies propose that cation-chloride cotransporters KCC (potassium-chloride cotransporter) and NKCC (sodium–potassium-chloride cotransporter), nonsynaptic mechanisms associated with chloride (Cl⁻) homeostasis, may be targets for anticonvulsant treatment. However, the contribution of these cotransporters to the neuronal activities during epileptiform discharges is not yet clear. This study aimed to investigate the effect of the cation-Cl⁻ cotransporters (KCC and NKCC) during non-synaptic epileptiform activity (NSEA) through mathematical modeling and computational simulations. The mathematical model represents electrochemical mechanisms of the granular layer of the dentate gyrus in the rat hippocampus, such as ion channels, the Na/K pump, KCC, NKCC, etc. For KCC and NKCC, in particular, ionic fluxes were estimated according to the Michaelis–Menten formalism, considering the reactions of their physiological ligands in an equilibrium state at each instant. Simulating experimental procedures, the results show that the blockage of both cotransporters is not enough to suppress non-synaptic epileptiform discharges after they have been triggered. According to the simulations, KCC and NKCC contribute to intracellular Cl⁻ accumulation and to increase neuronal excitability. However, the Cl⁻ flux through ionic channels is sufficient to maintain the intracellular Cl ⁻ concentration at the high level necessary to the occurrence of epileptiform discharges.