Elsevier

Ageing Research Reviews

Volume 3, Issue 4, November 2004, Pages 431-443
Ageing Research Reviews

Review
Reactive oxygen species and synaptic plasticity in the aging hippocampus

https://doi.org/10.1016/j.arr.2004.05.002Get rights and content

Abstract

Aging is associated with a general decline in physiological functions including cognitive functions. Given that the hippocampus is known to be critical for certain forms of learning and memory, it is not surprising that a number of neuronal processes in this brain area appear to be particularly vulnerable to the aging process. Long-term potentiation (LTP), a form of synaptic plasticity that has been proposed as a biological substrate for learning and memory, has been used to examine age-related changes in hippocampal synaptic plasticity. A current hypothesis states that oxidative stress contributes to age-related impairment in learning and memory. This is supported by a correlation between age, memory impairment, and the accumulation of oxidative damage to cellular macromolecules. However, it also has been demonstrated that ROS are necessary components of signal transduction cascades during normal physiological processes. This review discusses the evidence supporting the dual role of reactive oxygen species (ROS) as cellular messenger molecules in normal LTP, as well their role as damaging toxic molecules in the age-related impairment of LTP. In addition, we will discuss parallel analyses of LTP and behavioral tests in mice that overexpress antioxidant enzymes and how the role of antioxidant enzymes and ROS in modulating these processes may vary over the lifespan of an animal.

Introduction

Oxidative stress refers to the imbalance between the cellular production of reactive oxygen species (ROS) and the antioxidant mechanisms that remove them (Halliwell, 1992). Oxidative stress can result in damage to the cell via the oxidization of cellular components such as membrane lipids, proteins and DNA. The brain is particularly vulnerable to oxidative stress because it consumes large amounts of oxygen, has abundant lipid content, and a relative paucity of antioxidant levels compared to other organs (Halliwell, 1992). Numerous studies have reported correlations between age and the accumulation of oxidative damage to cellular macromolecules (for reviews, see Stadtman, 2001, Floyd and Hensley, 2002). For example aged rats exhibit enhanced lipid peroxidation (Gupta et al., 1991, Murray and Lynch, 1998b; O’Donnell and Lynch, 1998, Calabrese et al., 2004, Devi and Kiran, 2004) and protein oxidation (Sohal et al., 1994, Cini and Moretti, 1995, Forster et al., 1996) in their brains. Furthermore, it has been demonstrated that aged rats have increased oxidative damage to both nuclear and mitochondrial DNA (Hamilton et al., 2001). The strong correlation between increasing age and the accumulation of oxidative damage has largely supported the oxidative stress hypothesis of aging (for a review, see Beckman and Ames, 1998).

Several antioxidant mechanisms serve to counterbalance the potential deleterious effects of ROS. Among enzymatic scavengers of ROS are superoxide dismutase (SOD), catalase and glutathione peroxidase (GPX) (Halliwell, 1991, Brigelius-Flohe, 1999). SOD converts superoxide and H+ to hydrogen peroxide, which is then converted to water by either catalase or a variety of GPXs. There also are hydrophilic radical scavengers such as ascorbate (Vitamin C), urate, and glutathione, as well as lipophilic radical scavengers such as tocopherol (Vitamin E), carotenoids, and flavonoids. The increase in age-related oxidative damage could result from a multitude of factors, including a decrease in antioxidant defenses. Unfortunately, results from studies of antioxidant levels in the brain during aging are inconsistent. For example, decreases, increases, and lack of change in the levels of antioxidant enzymes have been reported in studies of aged animals (Table 1). This lack of consistency from study to study could be due to the species, strain, or the precise age of the animals being studied. Further complicating this issue, increases in the antioxidant defense mechanisms of an animal could be interpreted as either as an increase in protection from oxidative damage or an adaptation to deal with increases in oxidant generation. Age-related oxidative damage also may be due to an increase in ROS production. For example, it has been demonstrated that hippocampal slices from aged rats produce more hydrogen peroxide that younger rats (Auerbach and Segal, 1997, Murray and Lynch, 1998b; McGahon et al., 1999d; Driver et al., 2000, O’Donnell et al., 2000, Kamsler and Segal, 2003b). Another factor that can impact the accumulation of oxidative damage is the efficacy of the mechanisms necessary for the repair or degradation of the damaged molecules. Several studies have indicated that those mechanisms are diminished in the brain of aged animals (Edwards et al., 1998, Chen et al., 2002).

Although ROS have been shown to cause damage to protein, lipids and nucleic acids, there also is evidence that these molecules have normal regulatory actions. ROS have a major role in the modulation of cellular signal transduction pathways and gene expression in a variety of biological processes (for reviews, see Sen and Packer, 1996, Finkel, 2003, Esposito et al., 2004). ROS can activate a number of transcription factors (Flohe et al., 1997, Brigelius-Flohe et al., 2004), increase the activity of a number of protein kinases, and inactivate other enzymes such as protein phosphatases (for a review, see Klann and Thiels, 1999). One type of cellular process that appears to be tightly regulated by ROS is synaptic plasticity; the remainder of this review will focus on this issue.

Section snippets

The role of ROS in normal hippocampal synaptic plasticity

The hippocampus has been identified as a critical area for certain forms of learning and memory consolidation (for a review, see Morris et al., 2003). This has resulted in intense investigation of synaptic plasticity in this brain region. Long-term potentiation (LTP) is a long-lasting increase in the efficacy of synaptic transmission that has been proposed as a cellular substrate that could underlie mammalian learning and memory (Bliss and Collingridge, 1993, Malenka and Nicoll, 1999). The

Contribution of ROS to the age-related impairments in LTP and cognitive function

Impaired LTP and behavioral deficiency in learning and memory tasks are two of the hippocampal deficits observed in aging animals (for a review, see Barnes, 2003). Examination of differences between young and old brains has revealed higher levels of ROS as well as increased levels of oxidative stress markers in aging animals as compared to young animals (Sohal et al., 1994, Murray and Lynch, 1998a; McGahon et al., 1999d; Liu et al., 2003). Age-related LTP impairments in hippocampal area CA1 (

Possible signaling mechanisms mediating age-dependent alterations in LTP

Due to the increases in ROS during aging, it might be expected that the cellular signaling pathways activated during normal LTP could be altered by the oxidation of certain critical LTP effector molecules such as NMDA receptors, PKC, and protein phosphatases (Aizenman et al., 1990, Wang et al., 1996, Barrett et al., 1999, Watson et al., 2002). Thus, it will be of importance to examine the signaling cascades involved in LTP during aging and how they are influenced by ROS (Fig. 1). Marina Lynch

Conclusions

In this review we have discussed the role of ROS during hippocampal synaptic plasticity and memory. Collectively, the evidence suggests that the role of ROS in these processes differ depending on the particular ROS molecule and the age of the animal. For example, at young ages superoxide, and to a lesser degree hydrogen peroxide, are necessary for the full expression of LTP because their removal causes deficits in LTP. However, when higher concentrations of ROS are present, for example by

Acknowledgement

This work was supported by the National Institute of Health (NS34007 and T32-HL07676).

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