Control of neuronal plasticity by reactive oxygen species.
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Animals↗
Biomedical subjects
Ariel Kamsler
Publications and source records attributed to Ariel Kamsler.
Aged SOD overexpressing mice exhibit enhanced spatial memory while lacking hippocampal neurogenesis.
The recent finding that hippocampal slices from aged mice overexpressing the gene for superoxide dismutase (SOD) exhibit long-term potentiation (LTP) of reactivity to afferent stimulation that is significantly larger than that produced in aged wild-type (wt) mice has encouraged the exploration of the effects of reactive oxygen species (ROS) on learning in aged mice. In addition, young-adult and aged wt and SOD transgenic mice were used in an attempt to correlate adult neurogenesis with spatial learning. Aged wt and SOD mice exhibited a 90% reduction in doublecortin-labeled new dentate gyrus neurons as compared to young mice, with no significant difference between genotypes. In addition, aged SOD mice exhibited better performance than wt controls in both reference and working memory tasks in a water maze. These findings provide a behavioral measure to demonstrate that excessive production of H2O2 is beneficial in aged mice.
Aging↗
Functional and morphological alterations in compound transgenic mice overexpressing Cu/Zn superoxide dismutase and amyloid precursor protein [correction].
Down's syndrome (DS), the phenotypic manifestation of trisomy 21, involves overexpression of chromosome 21-encoded genes. The gene for amyloid precursor protein (APP), known to be involved in AD pathology, resides on chromosome 21 along with the gene for Cu/Zn superoxide dismutase (SOD1), a key enzyme in the metabolism of oxygen free radicals. We investigated the consequences of a combined increase in APP and SOD1, in a double-transgenic (tg)-APP-SOD1 mouse. These mice expressed severe impairment in learning, working and long-term memory. Expression of long-term potentiation in hippocampal slices was impaired in both tg-SOD and tg-APP-SOD mice, but not in tg-APP mice, indicating that increased APP by itself did not affect in vitro synaptic plasticity. In tg-APP-SOD mice, membrane-bound high molecular weight APP species accumulated while APP cleavage products did not increase and levels of secreted APP were unchanged. Severe morphological damage, including lipofuscin accumulation and mitochondria abnormalities, were found in aged tg-APP-SOD but not in the other mice. Thus, a combined elevation of the two chromosome 21 genes in tg-APP-SOD mice induced age-dependent alterations in morphological and behavioural functions.
Age Factors↗
Hydrogen peroxide as a diffusible signal molecule in synaptic plasticity.
Reactive oxygen species (ROS) have been considered for some time only in the context of oxidative stress-induced cell damage. In this review, we discuss the growing body of evidence that implicates ROS in general, and hydrogen peroxide (H2O2) in particular, in regulatory events underlying synaptic plasticity. H2O2 is regarded in this context as a specific diffusible signaling molecule. The action of H2O2 is assumed to be carried out via the release of calcium ions from internal stores, modulating the activity of specific calcium-dependent protein phosphatases. These phosphatases eventually affect neuronal plasticity. We discuss the role of H2O2 in these systems, stressing the importance of cellular regulation of H2O2 levels that are altered in aging individuals, in the ability to express plasticity. These studies highlight the function of H2O2 in processes of learning and memory and their change in elderly individuals, irrespective of neurodegeneration found in Alzheimer's patients.
Animals↗
Paradoxical actions of hydrogen peroxide on long-term potentiation in transgenic superoxide dismutase-1 mice.
Hydrogen peroxide (H2O2), a reactive oxygen species, is assumed to have a detrimental effect on neuronal plasticity. Indeed, H2O2 suppresses long-term potentiation (LTP) in hippocampal slices of normal rats and wild-type (wt) mice. Transgenic mice overexpressing superoxide dismutase (SOD) 1 (tg-SOD), which maintain high ambient H2O2, have also been shown to be impaired in their ability to express hippocampal LTP. Paradoxically, H2O2, at a concentration (50 microm) that blocks LTP in wt mice, actually enhanced LTP in slices of 2-month-old tg-SOD mice. H2O2-dependent LTP in tg-SOD was blocked by the protein phosphatase calcineurin inhibitor FK506, but not by rapamycin, an FK-binding protein 12 (FKBP12) inhibitor or by 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H7), a serine-kinase inhibitor. Interestingly, wt and tg-SOD mice expressed similar levels of the antioxidant enzyme catalase and similar activity of glutathione peroxidase. An opposite situation was found in 2-year-old mice. Aged wt mice were impaired in LTP in a manner that could be reversed by the addition of H2O2. Surprisingly, aged tg-SOD mice exhibited larger LTP than that found in wt mice, but this was now reduced by 50 microm H2O2. Both young tg-SOD and aged control mice displayed altered protein phosphatase activity, compared with that of young controls; moreover, FK506 inhibited LTP in old tg-SOD as well as in old wt mice treated with H2O2. These data promoted a dual role for H2O2 in the regulation of LTP, and proposed that it is mediated by the protein phosphatase calcineurin.
Age Factors↗
Hydrogen peroxide modulation of synaptic plasticity.
Unlike the proposed role of reactive oxygen species in neurodegeneration, acute effects of reactive oxygen on synaptic plasticity are poorly understood. Using rat hippocampal slices, we found that exposure to a high concentration (0.5-5 mm) of H(2)O(2) reduces EPSPs in both potentiated and nonpotentiated synapses. Exposure of the slices to 20 microm H(2)O(2) did not affect expression of preestablished long-term potentiation (LTP) but prevented induction of new LTP and enhanced long-term depression (LTD). Surprisingly, 1 microm H(2)O(2) caused a twofold increase in LTP compared with controls, and it further enhanced NMDA-independent LTP. A low concentration of H(2)O(2) also suppressed LTD. Nifedipine, an L-type calcium channel blocker, did not affect control LTP but blocked effects of both 1 and 20 microm H(2)O(2). Calcineurin inhibitors [FK506 (FR900506) and cyclosporin A but not rapamycin] acted similarly and also restored LTP in the presence of 20 microm H(2)O(2). These results suggest that H(2)O(2) alters NMDA-independent, voltage-gated calcium channel-mediated LTP by activating calcineurin.
Animals↗
Impaired interleukin-1 signaling is associated with deficits in hippocampal memory processes and neural plasticity.
The cytokine interleukin-1 (IL-1) is produced by peripheral immune cells as well as glia and neurons within the brain; it plays a major role in immune to brain communication and in modulation of neural, neuroendocrine, and behavioral systems during illness. Although previous studies demonstrated that excess levels of IL-1 impaired memory processes and neural plasticity, it has been suggested that physiological levels of IL-1 are involved in hippocampal-dependent memory and long-term potentiation (LTP). To examine this hypothesis, we studied IL-1 receptor type I knockout (IL-1rKO) mice in several paradigms of memory function and hippocampal plasticity. In the spatial version of the water maze test, IL-1rKO mice displayed significantly longer latency to reach a hidden platform, compared with wild-type controls. Furthermore, IL-1rKO exhibited diminished contextual fear conditioning. In contrast, IL-1rKO mice were similar to control animals in hippocampal-independent memory tasks; i.e., their performance in the visually guided task of the water maze and the auditory-cued fear conditioning was normal. Electrophysiologically, anesthetized IL-1rKO mice exhibited enhanced paired-pulse inhibition in response to perforant path stimulation and no LTP in the dentate gyrus. In vitro, decreased paired-pulse responses, as well as a complete absence of LTP, were observed in the CA1 region of hippocampal slices taken from IL-1rKO mice compared with WT controls. These results suggest that IL-1 contributes to the regulation of memory processes as well as short- and long-term plasticity within the hippocampus. These findings have important implications to several conditions in humans, which are associated with long-term defects in IL-1 signaling, such as mutations in the IL-1 receptor accessory protein-like gene, which are involved in a frequent form of X-linked mental retardation.
Animals↗