Modulation of GABAA Receptor Function by Ascorbic Acid

Purpose: Ascorbic acid, commonly known as vitamin C, is a vital antioxidant in the brain and is present in millimolar concentrations in neuron-rich areas. Ascorbic acid has numerous functions including modulation of neurotransmission and maintaining redox balance. It has been shown to protect neurons from excitotoxicity induced by activation of the NMDA receptors. While neuronal excitability reflects a balance between excitation and inhibition, GABA is the main inhibitory neurotransmitter that binds to GABAA receptors and reduces neuronal excitability. The purpose of the present study is to determine whether ascorbic acid influences GABAA receptor function. Methods: Whole-cell currents were recorded with patch clamp technique from human embryonic kidney cell line (HEK 293) stably expressing recombinant human a1b2g2 GABAA receptor which is the most abundant form of GABAA receptors in the brain. Results: Ascorbic acid alone did not induce any current. However, when co-applied with 3 mM GABA, ascorbic acid concentration-dependently increased GABA response with an EC50 value of 201 mM and an efficacy of 231%. Ascorbic acid induced similar potentiation of the currents activated by muscimol, a GABAA receptor agonist. Pre-treatment with 100 mM ascorbic acid for 10 sec caused a persistent enhancement in GABA response. The potentiating effect on GABA-activated currents was also induced by D-isoascorbic acid, a steroisomer of ascorbic acid with similar antioxidant property. Conclusions: Ascorbic acid modulates GABAA receptor function and this effect is partially mediated by a redox-dependent mechanism. Furthermore, the enhancement of GABAergic inhibition by ascorbic acid can potentially contribute to neuroprotection against excitotoxicity.