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The Journal of Neuroscience, April 12, 2006, 26(15):3933-3941; doi:10.1523/JNEUROSCI.5566-05.2006
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Neurobiology of Disease
Aging-Dependent Alterations in Synaptic Plasticity and Memory in Mice That Overexpress Extracellular Superoxide Dismutase
Daoying Hu,1 Faridis Serrano,1 Tim D. Oury,3 andEric Klann1,2 Departments of 1Molecular Physiology and Biophysics and 2Neuroscience, Baylor College of Medicine, Houston, Texas 77030, and 3Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15261
Correspondence should be addressed to Dr. Eric Klann, Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, BCM 335, Houston, TX 77030. Email: eklann{at}bcm.tmc.edu
Oxidative damage caused by reactive oxygen species (ROS) has been proposed to be critically involved in several pathological manifestations of aging, including cognitive dysfunction. ROS, including superoxide, are generally considered as neurotoxic molecules whose effects can be alleviated by antioxidant enzymes. However, ROS also are known to be necessary components of the signal transduction cascades underlying normal synaptic plasticity. Therefore, we reasoned that the role that ROS and antioxidant enzymes play in modulating neuronal processes varies over the lifespan of an animal. We examined hippocampal long-term potentiation (LTP) and memory-related behavioral performance in transgenic mice overexpressing extracellular superoxide dismutase (EC-SOD) and their wild-type littermates at different ages. We found that aged EC-SOD transgenic mice exhibited enhanced hippocampal LTP, better cerebellum-dependent motor learning, and better hippocampus-dependent spatial learning compared with their wild-type littermates. We also found that EC-SOD overexpression impaired contextual learning, but the impairment was decreased in the aged transgenic mice. At the molecular level, aged EC-SOD transgenic mice had lower superoxide levels, a decrease in protein carbonyl levels, and a decrease in p38 and extracellular signal-regulated kinase 2 phosphorylation compared with aged wild-type mice. Our findings suggest that elevated levels of superoxide contribute to aging-related impairments in hippocampal LTP and memory, and that these impairments can be alleviated by overexpression of EC-SOD. We conclude that there is an age-dependent alteration in the role of superoxide in modulating synaptic plasticity and learning and memory.
Key words: EC-SOD; superoxide; aging; oxidative stress; learning and memory; long-term potentiation
Received Aug. 26, 2005; revised Feb. 13, 2006; accepted March 3, 2006.
Correspondence should be addressed to Dr. Eric Klann, Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, BCM 335, Houston, TX 77030. Email: eklann{at}bcm.tmc.edu
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