title: Hydrogen peroxide increases GABAA receptor-mediated tonic current in hippocampal neurons.
abstract: Hydrogen peroxide (H2O2), a key reactive oxygen species, is produced at low levels during normal cellular metabolism and at higher concentrations under pathological conditions such as ischemia-reperfusion injury. The mechanisms by which H2O2 contributes to physiological and pathological processes in the brain remain poorly understood. Inhibitory GABA type A (GABAA) receptors critically regulate brain function by generating tonic and synaptic currents; however, it remains unknown whether H2O2 directly modulates GABAA receptor function. Here, we performed patch-clamp recordings, together with pharmacological and genetic approaches, to investigate the effects of H2O2 on GABAA receptor-mediated tonic and synaptic currents recorded in cultured mouse hippocampal neurons and CA1 pyramidal neurons in hippocampal slices. We found that H2O2 caused a dramatic increase in tonic current, whereas synaptic currents were unaffected. This increase in tonic current resulted from an extracellular oxidative reaction, which increased the potency of GABA, but only when GABAA receptors were activated by low concentrations of GABA. Oxygen-glucose deprivation, which produces high endogenous levels of H2O2, similarly increased the tonic current. These results suggest that GABAA receptor-mediated tonic current, which is potentiated by H2O2, might contribute to H2O2-induced brain dysfunction.
authors.affiliation: Departments of Physiology and.
authors.forename: Antonello
authors.initials: A
authors.lastname: Penna
authors.affiliation: Departments of Physiology and.
authors.forename: Dian-Shi
authors.initials: DS
authors.lastname: Wang
authors.affiliation: Departments of Physiology and.
authors.forename: Jieying
authors.initials: J
authors.lastname: Yu
authors.affiliation: Departments of Physiology and.
authors.forename: Irene
authors.initials: I
authors.lastname: Lecker
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec H3G 1Y6, Canada.
authors.forename: Patricia M G E
authors.initials: PM
authors.lastname: Brown
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec H3G 1Y6, Canada.
authors.forename: Derek
authors.initials: D
authors.lastname: Bowie
authors.affiliation: Departments of Physiology and Anesthesia, University of Toronto, Toronto, Ontario M5S 1A8, Canada, Department of Anesthesia, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada, and beverley.orser@utoronto.ca.
authors.forename: Beverley A
authors.initials: BA
authors.lastname: Orser
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D005947:Glucose / Q000172:deficiency; D006624:Hippocampus / Q000166:cytology*; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D000860:Hypoxia / Q000473:pathology / Q000503:physiopathology; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects*; D016877:Oxidants / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*
chemical_list: C496250:Gabra5 protein, mouse; D016877:Oxidants; D017382:Reactive Oxygen Species; D011963:Receptors, GABA-A; D006861:Hydrogen Peroxide; D005947:Glucose
keywords: GABAA receptor; hippocampus; hydrogen peroxide; ischemia-reperfusion; mouse; tonic current
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