title: Age-related deficits in long-term potentiation are insensitive to hydrogen peroxide: coincidence with enhanced autophosphorylation of Ca2+/calmodulin-dependent protein kinase II.
abstract: 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 H(2)O(2) (580 micro M) significantly inhibited LTP in young mice; a similar dose of H(2)O(2) 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 H(2)O(2). Western immunoblotting studies in young mice show that the relative levels of autophosphorylated alpha-Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) are unchanged in hippocampal CA1 treated with H(2)O(2) relative to untreated controls. However with aging, there is a significant enhancement in the levels of autophosphorylated CaMKII in H(2)O(2)-treated CA1 of older mice. Phosphorylation of RC3/neurogranin (Ng) by protein kinase C (PKC) is decreased in CA1 in response to H(2)O(2) treatment, irrespective of age. We propose that, during aging, enhanced local release of H(2)O(2) from mitochondria may induce a compensatory "ceiling" effect at synapses, so that the levels of autophosphorylated alpha CaMKII are aberrantly saturated, leading to alterations in synaptic plasticity.
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, UCLA School of Medicine, Los Angeles, California, USA. jwatson@mednet.ucla.edu
authors.forename: J B
authors.initials: JB
authors.lastname: Watson
authors.forename: H
authors.initials: H
authors.lastname: Khorasani
authors.forename: A
authors.initials: A
authors.lastname: Persson
authors.forename: K-P
authors.initials: KP
authors.lastname: Huang
authors.forename: F L
authors.initials: FL
authors.lastname: Huang
authors.forename: T J
authors.initials: TJ
authors.lastname: O'Dell
mesh_terms: D000375:Aging / Q000187:drug effects / Q000378:metabolism*; D000544:Alzheimer Disease / Q000201:enzymology* / Q000503:physiopathology; D000818:Animals; D000831:Animals, Newborn; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D002148:Calmodulin-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D006861:Hydrogen Peroxide / Q000378:metabolism* / Q000494:pharmacology; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000378:metabolism; D051579:Neurogranin; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000201:enzymology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D002148:Calmodulin-Binding Proteins; D009419:Nerve Tissue Proteins; C496650:Nrgn protein, mouse; D017382:Reactive Oxygen Species; D051579:Neurogranin; D006861:Hydrogen Peroxide; D011493:Protein Kinase C; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases