Role of antioxidant enzymes in redox regulation of N-methyl-D-aspartate receptor function and memory in middle-aged rats

NEUROBIOLOGY OF AGING

卷:35

Article

Lee, Wei-Hua¹  Kumar, Ashok²  Rani, Asha²  Foster, Thomas C.² 

[1] Univ Wisconsin, Dept Med Genet, Madison, WI 53706 USA

[2] Univ Florida, McKnight Brain Inst, Dept Neurosci, Gainesville, FL 32610 USA

关键词: Aging;    Superoxide dismutase;    Catalase;    Glutathione peroxidase;    Learning and memory;    NMDAR;    Synaptic plasticity;   

DOI  :  10.1016/j.neurobiolaging.2013.12.002

来源: Elsevier

【 摘 要 】

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. (C) 2014 Elsevier Inc. All rights reserved.

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