Double-edged GABAergic synaptic transmission in seizures: The importance of chloride plasticity.

GABAergic synaptic inhibition, which is a critical regulator of neuronal excitability, is closely involved in epilepsy. Interestingly, fast GABAergic transmission mediated by Cl permeable GABA receptors can bi-directionally exert both seizure-suppressing and seizure-promoting actions. Accumulating evidence suggests that chloride plasticity, the driving force of GABA receptor-mediated synaptic transmission, contributes to the double-edged role of GABAergic synapses in seizures. Large amounts of Cl influx can overwhelm Cl extrusion during seizures not only in healthy tissue in a short-term "activity-dependent" manner, but also in chronic epilepsy in a long-term, irreversible "pathology-dependent" manner related to the dysfunction of two chloride transporters: the chloride importer NKCC1 and the chloride exporter KCC2. In this review, we address the importance of chloride plasticity for the "activity-dependent" and "pathology-dependent" mechanisms underlying epileptic events and provide possible directions for further research, which may be clinically important for the design of GABAergic synapse-targeted precise therapeutic interventions for epilepsy.