Aging-Dependent Alterations in Synaptic Plasticity and Memory in Mice That Overexpress Extracellular Superoxide Dismutase

Abstract

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.

Overexpression of SOD-2 reduces hippocampal superoxide and prevents memory deficits in a mouse model of Alzheimer's disease

“…1 A). We then measured the levels of superoxide in the hippocampus by using dihydroethidium (DHE) staining (16). We found that Tg2576 mice exhibited higher levels of hippocampal superoxide compared with WT littermates (Fig.…”

“…DHE was obtained from Molecular Probes. To identify superoxide formation in the brain, DHE was used as previously described (16). Briefly, DHE-injected animals were cardiac-perfused with 4% paraformaldehyde, their were brains sectioned on a cryostat, and then sections were mounted with Vectashield H1200 containing DAPI (Vector Laboratories).…”

Comparison of lifelong and late life exercise on oxidative stress in the cerebellum

“…This series of studies addresses a basic question regarding the mechanism by which lifelong exercise can act to limit the extent of cerebellar damage [1,20,31] and loss of cerebellar motor function [9,19]. These results indicate that aging is coupled to an increase in cerebellar oxidative damage for a broad array of molecules.…”

Hippocampal long-term potentiation, memory, and longevity in mice that overexpress mitochondrial superoxide dismutase

“…Our recent work on another SOD isozyme, extracellular SOD (EC-SOD), revealed that EC-SOD overexpression improves hippocampal synaptic plasticity and memory-related behavioral performance in aged mice (Hu, Serrano, Oury, & Klann, 2006). In light of our observations with EC-SOD transgenic mice, we utilized SOD-2 overexpressing mice to examine the role of mitochondrial superoxide on hippocampal function during aging.…”