Postdepolarization Potentiation of GABAA Receptors: A Novel Mechanism Regulating Tonic Conductance in Hippocampal Neurons

摘要

Ambient GABA in the brain activates GABAA receptors to produce tonic inhibition. Membrane potential influences both GABA transport and GABAA receptors and could thereby regulate tonic inhibition. We investigated the voltage dependence of tonic currents in cultured rat hippocampal neurons using patch-clamp techniques. Tonic GABAA conductance increased with depolarization from 15 ± 3 pS/pF at −80 mV to 29 ± 5 pS/pF at −40 mV. Inhibition of vesicular or nonvesicular GABA release did not prevent voltage-dependent increases of tonic conductance. Currents evoked with exogenous GABA (1 μm) were outwardly rectifying, similar to tonic currents caused by endogenous GABA. These results indicate that the voltage-dependent increase of tonic conductance was attributable to intrinsic GABAA receptor properties rather than an elevation of ambient GABA. After transient depolarization to +40 mV, endogenous tonic currents measured at −60 mV were increased by 75 ± 17%. This novel form of tonic current modulation, termed postdepolarization potentiation (PDP), recovered with a time constant of 63 s, was increased by exogenous GABA and inhibited by GABAA receptor antagonists. Measurements of EGABA showed PDP was caused by increased conductance and not a change in the anion gradient. To assess the functional significance of PDP, we used voltage-clamp waveforms that replicated epileptiform activity. PDP was produced by this pathophysiological depolarization. These data show that depolarization produces prolonged potentiation of tonic conductance attributable to voltage-dependent properties of GABAA receptors. These properties are well suited to limit excitability during pathophysiological depolarization accompanied by rises in ambient GABA, such as occur during seizures and ischemia.