title: Diminishing glutathione availability and age-associated decline in neuronal excitability.
abstract: Oxidative stress is frequently implicated in diminished electrical excitability of aging neurons yet the foundations of this phenomenon are poorly understood. This study explored links between alterations in cellular thiol-redox state and age-associated decline in electrical excitability in identified neurons (right pedal dorsal 1 [RPeD1]) of the gastropod Lymnaea stagnalis. Intracellular thiol redox state was modulated with either dithiothreitol or membrane permeable ethyl ester of the antioxidant glutathione (et-GSH). Neuronal antioxidant demand was manipulated through induction of lipid peroxidation with 2,2'-azobis-2-methyl-propanimidamide-dihydrochloride (AAPH). Glutathione synthesis was manipulated with buthionine sulfoximine (BSO). We show that; glutathione content of snail brains declines with age, whereas pyroglutamate content increases; treatment with AAPH and BSO alone aggravated the natural low excitability state of old RPeD1, but only the combination of AAPH + BSO affected electrical excitability of young RPeD1; et-GSH reversed this effect in young RPeD1; et-GSH and dithiothreitol treatment reversed age-associated low excitability of old RPeD1. Together, these data argue for a tight association between glutathione availability and the regulation of neuronal electrical excitability and indicate perturbation of cellular thiol-redox metabolism as a key factor in neuronal functional decline in this gastropod model of biological aging.
authors: Department of Biological Sciences, Faculty of Science, University of Calgary, Calgary, Alberta, Canada.
authors: Shawn N
authors: SN
authors: Watson
authors: Department of Biological Sciences, Faculty of Science, University of Calgary, Calgary, Alberta, Canada.
authors: Jonathon R
authors: JR
authors: Lee
authors: Department of Biological Sciences, Faculty of Science, University of Calgary, Calgary, Alberta, Canada.
authors: Tara E
authors: TE
authors: Risling
authors: Department of Biological Sciences, Faculty of Science, University of Calgary, Calgary, Alberta, Canada.
authors: Petra M
authors: PM
authors: Hermann
authors: Department of Biological Sciences, Faculty of Science, University of Calgary, Calgary, Alberta, Canada; Department of Physiology and Pharmacology, Faculty of Medicine, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada. Electronic address: wilderin@ucalgary.ca.
authors: Willem C
authors: WC
authors: Wildering
mesh_terms: D000200:Action Potentials; D000375:Aging / Q000378:metabolism* / Q000502:physiology*; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002478:Cells, Cultured; D005978:Glutathione / Q000378:metabolism*; D008195:Lymnaea; D008564:Membrane Potentials; D023421:Models, Animal; D009474:Neurons / Q000502:physiology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology
chemical_list: D005978:Glutathione
keywords: Aging; Electrophysiology; Glutathione imaging; Identified neuron; Lipid peroxidation; Lymnaea stagnalis; Mollusk; Neuronal excitability; Oxidative stress; Pyroglutamate; Redox balance; γ-Glutamylcysteine synthetase inhibition