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Postdepolarization potentiation of GABAA receptors: a novel mechanism regulating tonic conductance in hippocampal neurons.

ABSTRACT: 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 mum) 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.

SUBMITTER: Ransom CB

PROVIDER: S-EPMC2902370 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Postdepolarization potentiation of GABAA receptors: a novel mechanism regulating tonic conductance in hippocampal neurons.

Ransom Christopher B CB Wu Yuanming Y Richerson George B GB

The Journal of neuroscience : the official journal of the Society for Neuroscience 20100601 22

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 p ...[more]

PMID: 20519542

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Project description:GABA is a principal neurotransmitter in the hypothalamic suprachiasmatic nucleus (SCN) that contributes to intercellular communication between individual circadian oscillators within the SCN network and the stability and precision of the circadian rhythms. GABA transporters (GAT) regulate the extracellular GABA concentration and modulate GABAA receptor (GABAAR)-mediated currents. GABA transport inhibitors were applied to study how GABAAR-mediated currents depend on the expression and function of GAT. Nipecotic acid inhibits GABA transport and induced an inward tonic current in concentration-dependent manner during whole cell patch-clamp recordings from SCN neurons. Application of either the selective GABA transporter 1 (GAT1) inhibitors NNC-711 or SKF-89976A, or the GABA transporter 3 (GAT3) inhibitor SNAP-5114, produced only small changes of the baseline current. Coapplication of GAT1 and GAT3 inhibitors induced a significant GABAAR-mediated tonic current that was blocked by gabazine. GAT inhibitors decreased the amplitude and decay time constant and increased the rise time of spontaneous GABAAR-mediated postsynaptic currents. However, inhibition of GAT did not alter the expression of either GAT1 or GAT3 in the hypothalamus. Thus GAT1 and GAT3 functionally complement each other to regulate the extracellular GABA concentration and GABAAR-mediated synaptic and tonic currents in the SCN. Coapplication of SKF-89976A and SNAP-5114 (50 µM each) significantly reduced the circadian period of Per1 expression in the SCN by 1.4 h. Our studies demonstrate that GAT are important regulators of GABAAR-mediated currents and the circadian clock in the SCN.NEW & NOTEWORTHY In the suprachiasmatic nucleus (SCN), the GABA transporters GAT1 and GAT3 are expressed in astrocytes. Inhibition of these GABA transporters increased a tonic GABA current and reduced the circadian period of Per1 expression in SCN neurons. GAT1 and GAT3 showed functional cooperativity: inhibition of one GAT increased the activity but not the expression of the other. Our data demonstrate that GABA transporters are important regulators of GABAA receptor-mediated currents and the circadian clock.

Dataset Information

Postdepolarization potentiation of GABAA receptors: a novel mechanism regulating tonic conductance in hippocampal neurons.

Publications

Postdepolarization potentiation of GABAA receptors: a novel mechanism regulating tonic conductance in hippocampal neurons.

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