Peroxide Modulation of Slow Onset Potentiation in Rat Hippocampus

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Abstract
Exposure of rat hippocampal slices to low concentrations of the muscarinic agonist carbachol (CCh) has been shown to produce a slow onset long-term potentiation (LTP) of reactivity to afferent stimulation in CA1 neurons. Although this potentiation shares a number of properties with tetanic LTP, muscarinic LTP (LTPm) is independent of activation of the NMDA receptor. We now demonstrate that low levels of hydrogen peroxide (H2O2) cause hippocampal slices to lose the ability to express LTPm. This powerful effect of H2O2is selective in that it does not affect the reactivity of hippocampal neurons to higher concentrations of CCh. In fact, H2O2also blocks induction of a slow onset, non-NMDA-dependent tetanic LTP (NN-LTP). The functional relevance of this action of H2O2is exemplified by the fact that the hippocampus of aged rats, which produces higher levels of endogenous H2O2than that of young rats, lacks LTPmand expresses a markedly reduced NN-LTP. In aged rats, the lack of LTPmcontrasts with an apparently normal muscarinic suppression of the EPSP slope induced by higher concentrations of CCh. When hippocampal slices from aged animals are treated with catalase, an enzyme that breaks down H2O2, LTPmis restored, and NN-LTP is enhanced. Thus, our study proposes a unique and novel age-dependent peroxide regulation of LTPmin the brain and provides a link between the cholinergic system, aging, and memory functions.