Intracellular Redox State Alters NMDA Receptor Response during Aging through Ca2+/Calmodulin-Dependent Protein Kinase II

Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, Florida 32610, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 02/2010; 30(5):1914-24. DOI: 10.1523/JNEUROSCI.5485-09.2010
Source: PubMed


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.

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    • "Redox changes (i.e. alterations in the oxidation-reduction status) affect NMDAR synaptic responses and NMDAR-dependent LTP and cognition (Bodhinathan et al., 2010; Robillard et al., 2011; Ghosh et al., 2012; Haxaire et al., 2012; Lee et al., 2012). SOD1 is a cytosolic enzyme that functions as an antioxidant and plays an essential role in normal metal homeostasis. "
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    • "There is evidence showing that NMDA receptor function depends on intracellular redox state, possibly through changes in CaMKII activity. In particular, it was shown that intracellular application of glutathione increases NMDA receptor responses and restores NMDA-dependent long term potentiation in aged mice (Bodhinathan et al. 2010; Robillard et al. 2011). EACC1 transporters expressed in postsynaptic dendrites close to synapses may help maintain redox buffering capacities at levels high enough for proper NMDA receptor functioning. "
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    • "In particular, it is known that the function of the NMDA receptor relies on the thiol redox state of the cell, which in turn, is influenced by GSH concentration. GSH can modulate the redox state of the NMDA receptor, causing an increase in its activity (Tang and Aizenman, 1993; Janaky et al., 1999; Bodhinathan et al., 2010) and suggesting that increasing GSH may be beneficial in restoring LTP. In agreement with this model, Yang et al. (2010) discovered that the deficits in hippocampal CA1 LTP that are induced by aging could be reversed by the reductants dithiothreitol and b-mercaptoethanol. "
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