Intracellular Cl^- dysregulation causing and caused by pathogenic neuronal activity

The intracellular Cl^- concentration ([Cl^-]_i) is tightly regulated in brain neurons for stabilizing brain performance. The [Cl^-]_i in mature neurons is determined by the balance between the rate of Cl^- extrusion mainly mediated by the neuron-specific type 2 K⁺-Cl^- cotransporter (KCC2) and the rate of Cl^- entry through various Cl^- channels including GABA_A receptors during neuronal activity. Disturbance of the balance causes instability of brain circuit performance and may lead to epileptic seizures. In the first part of this review, we discuss how genetic alterations in KCC2 in humans cause infantile migrating focal seizures, based on our previous report and others. Depolarization of the membrane potential increases the driving force for Cl^- entry into neurons. Thus, the duration of action potential spike generation and the frequency of excitatory synaptic inputs are the crucial factors for determining the total amount of Cl^- entry and the equilibrium [Cl^-]_i in neurons. Moreover, there is also a significant interdependence between the neuronal activity and the KCC2 expression. In the second part, we discuss plausible mechanisms by which excessive neuronal activity due to excitotoxic brain insults or other epilepsy-associated gene mutations may cause the Cl^- imbalance in neurons and lead to epileptic discharges over the brain, using the schematic "unifying foci" model based on literature.