Chloride homeostasis and GABA signaling in temporal lobe epilepsy

Changes in neuronal chloride homeostasis affect GABA receptor-mediated transmission and may contribute to epileptic activities. Work on human epileptic tissue suggests that Cl homeostasis is impaired in some temporal lobe pyramidal cells. GABAergic depolarization of these neurons contributes to rhythmic, interictal events. Intra-neuronal Cl is controlled in part by two electroneutral cation-chloride cotransporters. NKCC1 mediates Cl influx, while KCC2 extrudes Cl thus assuring that GABAergic signals hyperpolarize neurons. After stress, such as trauma or denervation, the expression and/or function of the cotransporters are altered. KCC2 is down-regulated in some pyramidal cells from both patients with temporal lobe epilepsy and animals with acquired focal epilepsies. The resulting depolarising GABAergic signals contribute to the generation of interictal-like activity. Is a defective Cl homeostasis also crucial for the genesis of ictal events? Ictal discharges are associated with intense interneuron firing and activation of GABA receptors. Depolarizing responses to GABA are evident during ictal events generated by convulsants in both animal epilepsy models and human tissue. K-Cl cotransport by KCC2 is increased by the Cl load in neurons. Paradoxically, the resulting increase in extracellular K generates a prolonged depolarization that may sustain seizure discharges.