GABAA-Receptor Signaling and Ionic Plasticity in the Generation and Spread of Seizures

Abstract

Abstract According to a classical concept in epilepsy research, seizures are triggered by an “imbalance” between excitatory (glutamatergic) and inhibitory (GABAergic) synaptic transmission. Recent work has shown, however, that not only the efficacy but also the qualitative mode of action of GABAergic signaling is controlled by ionic plasticity, which is mediated by activity-dependent changes in the driving force of currents across GABAA receptors (GABAARs). We will briefly describe the basics of neuronal Cl− and pH/HCO3− regulation, and the main functions of neuronal carbonic anhydrases and the Cl− transporters, KCC2 and NKCC1. A major topic of discussion is how depolarizing currents carried by bicarbonate and by sodium across GABAARs and ionotropic glutamate receptors, respectively, act in a synergistic manner, leading to massive neuronal uptake of Cl− and large extracellular K+ transients. These transmembrane ion fluxes form a major constituent of a positive feedback cycle, in which neuronal excitability is boosted by, and contributes to, the ionic shifts. Initially, this leads to an erosion of the inhibitory restraint in the region surrounding the ictal core, followed by a subsequent transformation to functionally excitatory GABA action (which is independent on NKCC1). In line with this, a wealth of evidence shows that intense activation of cortical interneurons often has a seizure-promoting effect. The synaptic and non-synaptic mechanisms associated with GABAergic excitation shed light on the complex spatiotemporal profiles of seizure generation and propagation, and they provide a rational basis for the loss of efficacy of GABA-enhancing antiseizure drugs on ongoing seizure activity.