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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    • "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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    ABSTRACT: The excitatory amino acid carrier 1 (EAAC1) is a sodium-dependent glutamate transporter widely found in the mammalian brain and mainly localized in the somatodendritic compartment of neurons. The present study was performed to determine whether EAAC1 is present in the rat nucleus of the solitary tract (NST, a sensory brainstem nucleus involved in visceroception) and to document its subcellular localization. Using fluorescent immunolabeling, peroxidase immunostaining and quantitative immunogold labeling, we showed that both intracellular and plasma membrane-associated pools of EAAC1 transporters existed in dendrites of NST neurons. Although plasma membrane-associated transporters were more concentrated in the vicinity of synapses, no labeling was found at the axon–dendrite interface, suggesting that EAAC1 was not (or barely) expressed in this portion of dendritic membrane. Using computer simulation, we next showed that the ability of EAAC1 to efficiently take up synaptically released glutamate depended was very low outside the axon–dendrite interface. These data suggest that EAAC1 transporters present on NST dendrites may play a minor role if any in glutamate clearance.
    Brain Structure and Function 01/2015; DOI:10.1007/s00429-014-0958-7 · 5.62 Impact Factor
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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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    ABSTRACT: Previous studies from our laboratory have shown that prenatal ethanol exposure (PNEE) causes a significant deficit in synaptic plasticity, namely long-term potentiation (LTP), in the dentate gyrus (DG) region of the hippocampus of male rats. PNEE has also been shown to induce an increase in oxidative stress and a reduction in antioxidant capacity in the brains of both male and female animals. In this study the interaction between LTP and the major antioxidant in the brain, glutathione (GSH), is examined. We show that depletion of the intracellular reserves of GSH with diethyl maleate (DEM) reduces LTP in control male, but not female animals, mirroring the effects of PNEE. Furthermore, treatment of PNEE animals with N-acetyl cysteine (NAC), a cysteine donor for the synthesis of GSH, increases GSH levels in the hippocampus and completely restores the deficits in LTP in PNEE males. These results indicate that in males GSH plays a major role in regulating LTP, and that PNEE may cause reductions in LTP by reducing the intracellular pool of this endogenous antioxidant. © 2013 Wiley Periodicals, Inc.
    Hippocampus 12/2013; 23(12). DOI:10.1002/hipo.22199 · 4.16 Impact Factor
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    • "ox shift and generation of excessive ROS , but the transcriptional and receptor effects of the redox shift may be more important than any repairable ROS damage ( Brewer , 2010a ) . In support of this redox balance concept , Kanninen et al . ( 2009 ) showed that vector - mediated Nrf2 expression in hippocampus improved cognition in APP / PS1 mice . Bodhinathan et al . ( 2010a , 2010b ) found intracellular redox state to enhance N - methyl - D - aspartate ( NMDA receptor activity , long - term potentiation ( LTP ) , and better - control calcium dynamics in aged but not young mouse ."
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    ABSTRACT: To determine whether glutathione (GSH) loss or increased reactive oxygen species (ROS) are more important to neuron loss, aging, and Alzheimer's disease (AD), we stressed or boosted GSH levels in neurons isolated from aging 3xTg-AD neurons compared with those from age-matched nontransgenic (non-Tg) neurons. Here, using titrating with buthionine sulfoximine, an inhibitor of γ-glutamyl cysteine synthetase (GCL), we observed that GSH depletion increased neuronal death of 3xTg-AD cultured neurons at increasing rates across the age span, whereas non-Tg neurons were resistant to GSH depletion until old age. Remarkably, the rate of neuron loss with ROS did not increase in old age and was the same for both genotypes, which indicates that cognitive deficits in the AD model were not caused by ROS. Therefore, we targeted for neuroprotection activation of the redox sensitive transcription factor, nuclear erythroid-related factor 2 (Nrf2) by 18 alpha glycyrrhetinic acid to stimulate GSH synthesis through GCL. This balanced stimulation of a number of redox enzymes restored the lower levels of Nrf2 and GCL seen in 3xTg-AD neurons compared with those of non-Tg neurons and promoted translocation of Nrf2 to the nucleus. By combining the Nrf2 activator together with the NADH precursor, nicotinamide, we increased neuron survival against amyloid beta stress in an additive manner. These stress tests and neuroprotective treatments suggest that the redox environment is more important for neuron survival than ROS. The dual neuroprotective treatment with nicotinamide and an Nrf2 inducer indicates that these age-related and AD-related changes are reversible.
    Neurobiology of aging 08/2013; 35(1). DOI:10.1016/j.neurobiolaging.2013.06.023 · 5.01 Impact Factor
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