Molecular Manipulations of Extracellular Superoxide Dismutase: Functional Importance for Learning |
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Authors: | Edward D Levin Todd C Brady Elizabeth Crapo Hochrein Tim D Oury Lena M Jonsson Stefan L Marklund James D Crapo |
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Institution: | (1) Departments of Psychiatry, Pharmacology and Integrated Toxicology Program, Nicholas School of the Environment, Duke University, Durham, North Carolina, USA;(2) Dr. Edward Levin, Neurobehavioral Research Laboratory, Department of Psychiatry, Duke University Medical Center, Durham, North Carolina 27710, USA;(3) Department of Pathology, Integrated Toxicology Program, Duke University, Durham, North Carolina, USA;(4) Department of Medicine, Duke University, Durham, North Carolina, USA;(5) Departments of Psychiatry and Pathology, Duke University, Durham, North Carolina, USA;(6) Departments of Clinical Chemistry and Microbiology, University of Umeå, Umeå, Sweden;(7) Department of Clinical Chemistry, University of Umeå, Umeå, Sweden;(8) National Jewish Medical and Research Center, Denver, Colorado, USA |
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Abstract: | Extracellular superoxide dismutase (EC-SOD) controls the availability of extracellular superoxide (O
2
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), which is important for a variety of physiological pathways, including the primary means of inactivating nitric oxide (NO). The role of EC-SOD in neurobehavioral function has been until now unexplored. In the current studies, the phenotypic expression of genotypic alterations of EC-SOD production in mice were characterized for spatial learning and memory. Dramatic impairments in spatial learning in the win-shift 8-arm radial maze were seen in both EC-SOD knockout mice and EC-SOD overexpressing mice. The EC-SOD overexpressing mice were further characterized as having significant deficits in a repeated acquisition task in the radial-arm maze, which permitted the dissociation of long and short-term learning. Long-term learning was significantly impaired by EC-SOD overexpression, whereas short-term learning was not significantly affected by EC-SOD overexpression. NO systems have been shown to be importantly involved in learning and memory. This may be important in the current studies because EC-SOD has primary control over the inactivation of NO. We found that EC-SOD overexpressing mice were resistant to the cognitive effects of L-NAME (NG-nitro-L-arginine methyl ester hydrochloride), an NO synthase inhibitor. Decreased NO catabolism in these mice may have served to counter the effects of NOS inhibition by L-NAME. The current finding that EC-SOD levels that were either higher or lower than controls impaired learning demonstrates that the proper control of brain extracellular (O
2
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) may be more vital than merely reduction of brain extracelluar (O
2
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) in maintaining adequate learning function. |
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Keywords: | Extracellular superoxide dismutase SOD memory learning radial-arm maze |
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