Intracellular redox state alters NMDA receptor response during aging through Ca2+/calmodulin-dependent protein kinase II.
The contribution of the NMDA receptors (NMDARs) to synaptic plasticity declines during aging, and the decline is thought to contribute to memory deficits. Here, we demonstrate that an age-related shift in intracellular redox state contributes to the decline in NMDAR responses through Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). The oxidizing agent xanthine/xanthine oxidase (X/XO) decreased the NMDAR-mediated synaptic responses at hippocampal CA3-CA1 synapses in slices from young (3-8 months) but not aged (20-25 months) rats. Conversely, the reducing agent dithiothreitol (DTT) selectively enhanced NMDAR response to a greater extent in aged hippocampal slices. The enhancement of NMDAR responses facilitated induction of long-term potentiation in aged but not young animals. The DTT-mediated growth in the NMDAR response was not observed for the AMPA receptor-mediated synaptic responses. A similar increase was observed by intracellular application of the membrane-impermeable reducing agent, L-glutathione (L-GSH), through the intracellular recording pipette, indicating that the increased NMDAR response was dependent on intracellular redox state. DTT enhancement of the NMDAR response was dependent on CaMKII activity and was blocked by the CaMKII inhibitor--myristoylated autocamtide-2-related inhibitory peptide (myr-AIP)--but not by inhibition of the activity of protein phosphatases--PP1 and calcineurin (CaN/PP2B) or protein kinase C. CaMKII activity assays established that DTT increased CaMKII activity in CA1 cytosolic extracts in aged but not in young animals. These findings indicate a link between oxidation of CaMKII during aging, a decline in NMDAR responses, and altered synaptic plasticity.
Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, Florida 32610, USA.
Karthik
K
Bodhinathan
Ashok
A
Kumar
Thomas C
TC
Foster
D000375:Aging / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism*; D009473:Neuronal Plasticity; D010084:Oxidation-Reduction; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism
D017382:Reactive Oxygen Species; D016194:Receptors, N-Methyl-D-Aspartate; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium