title: Role of antioxidant enzymes in redox regulation of N-methyl-D-aspartate receptor function and memory in middle-aged rats.
abstract: Overexpression of superoxide dismutase 1 (SOD1) in the hippocampus results in age-dependent impaired cognition and altered synaptic plasticity suggesting a possible model for examining the role of oxidative stress in senescent neurophysiology. However, it is unclear if SOD1 overexpression involves an altered redox environment and a decrease in N-methyl-D-aspartate receptor (NMDAR) synaptic function reported for aging animals. Viral vectors were used to express SOD1 and green fluorescent protein (SOD1 + GFP), SOD1 and catalase (SOD1 + CAT), or GFP alone in the hippocampus of middle-aged (17 months) male Fischer 344 rats. We confirm that SOD1 + GFP and SOD1 + CAT reduced lipid peroxidation indicating superoxide metabolites were primarily responsible for lipid peroxidation. SOD1 + GFP impaired learning, decreased glutathione peroxidase activity, decreased glutathione levels, decreased NMDAR-mediated synaptic responses, and impaired long-term potentiation. Co-expression of SOD1 + CAT rescued the effects of SOD1 expression on learning, redox measures, and synaptic function suggesting the effects were mediated by excess hydrogen peroxide. Application of the reducing agent dithiolthreitol to hippocampal slices increased the NMDAR-mediated component of the synaptic response in SOD1 + GFP animals relative to animals that overexpress SOD1 + CAT indicating that the effect of antioxidant enzyme expression on NMDAR function was because of a shift in the redox environment. The results suggest that overexpression of neuronal SOD1 and CAT in middle age may provide a model for examining the role of oxidative stress in senescent physiology and the progression of age-related neurodegenerative diseases.
authors.affiliation: Department of Medical Genetics, University of Wisconsin, Madison, WI, USA.
authors.forename: Wei-Hua
authors.initials: WH
authors.lastname: Lee
authors.affiliation: Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
authors.forename: Asha
authors.initials: A
authors.lastname: Rani
authors.affiliation: Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. Electronic address: Foster1@ufl.edu.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Foster
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D002374:Catalase / Q000502:physiology; D018450:Disease Progression; D006624:Hippocampus / Q000201:enzymology; D008297:Male; D008568:Memory / Q000502:physiology*; D019636:Neurodegenerative Diseases / Q000209:etiology*; D009473:Neuronal Plasticity; D009474:Neurons / Q000201:enzymology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology; D051381:Rats; D011916:Rats, Inbred F344; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism / Q000502:physiology*; D013482:Superoxide Dismutase / Q000502:physiology*; D000072105:Superoxide Dismutase-1; D013569:Synapses / Q000502:physiology
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D002374:Catalase; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
keywords: Aging; Catalase; Glutathione peroxidase; Learning and memory; NMDAR; Superoxide dismutase; Synaptic plasticity