Post-hypoxic changes in rat cortical neuron GABAA receptor function require L-type voltage-gated calcium channel activation

Hypoxia modifies GABAA receptor (GABAAR) function and can cause seizures, encephalopathy or myoclonus. To characterize the effects of hypoxia on neuronal GABAARs, we subjected rat cortical neurons to 1% O2 for 2, 4 or 8 h, followed by recovery times of 0-96 h, and used whole-cell and perforated patch-clamp recording to assess GABAAR currents and pharmacology. Hypoxic exposure for 4 h caused downregulation of maximal GABA current immediately following hypoxia and after 48 h recovery without changing the EC50 for GABA. Two- and eight-hour hypoxic exposures had inconsistent effects on GABAAR currents. Maximal diazepam potentiation was increased immediately following 4 h hypoxia, while potentiation by zolpidem was increased after 48 h recovery. Pentobarbital enhancement and zinc inhibition of GABA currents were unchanged. Hypoxia also caused a depolarizing shift in the reversal potential of GABA-induced Cl− currents after 24 h recovery. The L-type voltage-gated calcium channel (L-VGCC) blocker, nitrendipine, during hypoxia or control treatment prevented the reduction in GABAAR currents, and increased control currents over baseline. Nitrendipine also prevented the increase in zolpidem potentiation 48 h after hypoxia, and blocked the depolarizing shift in Cl− reversal potential 24 h after hypoxia. The effects of hypoxia on maximal GABAAR currents, zolpidem pharmacology and Cl− reversal potential thus require depolarization-induced calcium entry via L-VGCCs, and constitutive L-VGCC activity appears to reduce maximal GABAAR currents in control neurons via a calcium-dependent process. Calcium-dependent modulation of GABAAR currents via L-VGCCs may be a fundamental regulatory mechanism for GABA receptor function.