title: Decreases in mitochondrial reactive oxygen species initiate GABA(A) receptor-mediated electrical suppression in anoxia-tolerant turtle neurons.
abstract: Anoxia induces hyper-excitability and cell death in mammalian brain but in the anoxia-tolerant western painted turtle (Chrysemys picta bellii) neuronal electrical activity is suppressed (i.e. spike arrest), adenosine triphosphate (ATP) consumption is reduced, and cell death does not occur. Electrical suppression is primarily the result of enhanced γ-aminobutyric acid (GABA) transmission; however, the underlying mechanism responsible for initiating oxygen-sensitive GABAergic spike arrest is unknown. In turtle cortical pyramidal neurons there are three types of GABA(A) receptor-mediated currents: spontaneous inhibitory postsynaptic currents (IPSCs), giant IPSCs and tonic currents. The aim of this study was to assess the effects of reactive oxygen species (ROS) scavenging on these three currents since ROS levels naturally decrease with anoxia and may serve as a redox signal to initiate spike arrest. We found that anoxia, pharmacological ROS scavenging, or inhibition of mitochondrial ROS generation enhanced all three types of GABA currents, with tonic currents comprising ∼50% of the total current. Application of hydrogen peroxide inhibited all three GABA currents, demonstrating a reversible redox-sensitive signalling mechanism. We conclude that anoxia-mediated decreases in mitochondrial ROS production are sufficient to initiate a redox-sensitive inhibitory GABA signalling cascade that suppresses electrical activity when oxygen is limited. This unique strategy for reducing neuronal ATP consumption during anoxia represents a natural mechanism in which to explore therapies to protect mammalian brain from low-oxygen insults.
authors.affiliation: Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada, M5S 3G5.
authors.forename: David W
authors.initials: DW
authors.lastname: Hogg
authors.affiliation: Department of Zoology, University of British Columbia, Vancouver, BC, Canada, V6T 1Z4.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Pamenter
authors.affiliation: Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada, M5S 3G5.
authors.forename: David J
authors.initials: DJ
authors.lastname: Dukoff
authors.affiliation: Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada, M5S 3G5.|Ecology and Evolutionary Biology, University of Toronto, Toronto, Ontario, Canada, M5S 3G5.
authors.forename: Leslie T
authors.initials: LT
authors.lastname: Buck
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D005260:Female; D006861:Hydrogen Peroxide / Q000494:pharmacology; D000860:Hypoxia / Q000503:physiopathology*; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D010084:Oxidation-Reduction; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism* / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D055366:Synaptic Potentials / Q000502:physiology; D014426:Turtles / Q000502:physiology*
chemical_list: D017382:Reactive Oxygen Species; D011963:Receptors, GABA-A; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide