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

• Published in: The Journal of neuroscience Vol. 30; no. 22; pp. 7672 - 7684
• Main Authors: Ransom, Christopher B., Wu, Yuanming, Richerson, George B.
• Format: Journal Article
• Language: English
• Published: 02.06.2010
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.0290-10.2010

Ambient GABA in the brain activates GABA A receptors to produce tonic inhibition. Membrane potential influences both GABA transport and GABA A 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 GABA A 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 μ m ) 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 GABA A 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 GABA A receptor antagonists. Measurements of E GABA 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 GABA A 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.