Age-related deficits in long-term potentiation are insensitive to hydrogen peroxide:: Coincidence with enhanced autophosphorylation of Ca2+/calmodulin-dependent protein kinase II

Reactive oxygen species (ROS) can have deleterious effects for both normal aging and Alzheimer's disease (AD). We examined the hypothesis that synapses undergoing long-term potentiation (LTP) are preferentially at risk for ROS-mediated oxidative stress during aging. We observed age-dependent deficits in LTP induced by a high-frequency stimulation (HFS) protocol in the CA1 region of hippocampus from C57BL/6 mice. There was a significant difference between LTP measured over 60 min in young (1-2 months) and old (23-26 months) mice. In oxidative stress studies, exogenous H2O2 (580 muM) significantly inhibited LTP in young mice; a similar dose of H2O2 failed to inhibit LTP in slices from adult (2-4 months) or from old mice. The results show that there are significant deficits in LTP in aging mice, but such deficits are insensitive to H2O2. Western immunoblotting studies in young mice show that the relative levels of autophosphorylated alpha-Ca2+/calmodulin-dependent protein kinase 11 (CaMKII) are unchanged in hippocampal CA1 treated with H2O2 relative to untreated controls. However with aging, there is a significant enhancement in the levels of autophosphorylated CaMKII in H2O2-treated CA1 of older mice. Phosphorylation of RC3/neurogranin (Ng) by protein kinase C (PKC) is decreased in CA1 in response to H2O2 treatment, irrespective of age. We propose that, during aging, enhanced local release of H2O2 from mitocohondria may induce a compensatory "ceiling" effect at synapses, so that the levels of auto phosphorylated alphaCaMKII are aberrantly saturated, leading to alterations in synaptic plasticity. (C) 2002 Wiley-Liss, Inc.