title: Hydrogen peroxide modulates neuronal excitability and membrane properties in ventral horn neurons of the rat spinal cord.
abstract: Hydrogen peroxide (H2O2), a reactive oxygen species, is an important signaling molecule for synaptic and neuronal activity in the central nervous system; it is produced excessively in brain ischemia and spinal cord injury. Although H2O2-mediated modulations of synaptic transmission have been reported in ventral horn (VH) neurons of the rat spinal cord, the effects of H2O2 on neuronal excitability and membrane properties remain poorly understood. Accordingly, the present study investigated such effects using a whole-cell patch-clamp technique. The bath-application of H2O2 decreased neuronal excitability accompanied by decreased input resistance, firing frequency, and action potential amplitude and by increased rheobase. These H2O2-mediated changes were induced by activation of extrasynaptic, but not synaptic, GABAA receptors. Indeed, GABAergic tonic currents were enhanced by H2O2. On the other hand, the amplitude of medium and slow afterhyperpolarization (mAHP and sAHP), which plays important roles in controlling neuronal excitability and is mediated by small-conductance calcium-activated potassium (SK) channels, was significantly decreased by H2O2. When extrasynaptic GABAA receptors were completely blocked, these decreases of mAHP and sAHP persisted, and H2O2 increased excitability, suggesting that H2O2 per se might have the potential to increase neuronal excitability via decreased SK channel conductance. These findings indicate that activating extrasynaptic GABAA receptors or SK channels may attenuate acute neuronal damage caused by H2O2-induced hyperexcitability and therefore represent a novel therapeutic target for the prevention and treatment of H2O2-induced motor neuron disorders.
authors.affiliation: Division of Orthopedic Surgery, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi Dori, Chuo-Ku, Niigata City 951-8510, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ohashi
authors.affiliation: Division of Orthopedic Surgery, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi Dori, Chuo-Ku, Niigata City 951-8510, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Hirano
authors.affiliation: Division of Orthopedic Surgery, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi Dori, Chuo-Ku, Niigata City 951-8510, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Watanabe
authors.affiliation: Division of Orthopedic Surgery, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi Dori, Chuo-Ku, Niigata City 951-8510, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Shoji
authors.affiliation: Division of Anesthesiology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi Dori, Chuo-Ku, Niigata City 951-8510, Japan.
authors.forename: Nobuko
authors.initials: N
authors.lastname: Ohashi
authors.affiliation: Division of Anesthesiology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi Dori, Chuo-Ku, Niigata City 951-8510, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Baba
authors.affiliation: Division of Orthopedic Surgery, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi Dori, Chuo-Ku, Niigata City 951-8510, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Endo
authors.affiliation: Division of Anesthesiology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi Dori, Chuo-Ku, Niigata City 951-8510, Japan. Electronic address: kohno-t@umin.net.
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Kohno
mesh_terms: D000818:Animals; D000870:Anterior Horn Cells / Q000187:drug effects / Q000502:physiology*; D001640:Bicuculline / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006861:Hydrogen Peroxide / Q000378:metabolism* / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology*; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D018377:Neurotransmitter Agents / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism; D018009:Receptors, Glycine / Q000378:metabolism; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism; D013331:Strychnine / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D046509:Tissue Culture Techniques; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000494:pharmacology
chemical_list: D018377:Neurotransmitter Agents; D011963:Receptors, GABA-A; D018009:Receptors, Glycine; D051640:Small-Conductance Calcium-Activated Potassium Channels; D005680:gamma-Aminobutyric Acid; D006861:Hydrogen Peroxide; D013331:Strychnine; D001640:Bicuculline
keywords: afterhyperpolarization; extrasynaptic GABA(A) receptor; patch clamp; small-conductance calcium-activated potassium channel; tonic current