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

“Introduction The NMDA receptor (NMDAR) is a major source of Ca 2 influx into the postsynaptic neuron during the induction of LTP at hippocampal CA3–CA1 synapses (Bliss and Collingridge, 1993).”

“The interaction of NMDARs with CaMKII has been proposed as a model of memory (Lisman et al., 2002) and recent work indicates that disruption of the interaction between CaMKII and NMDAR impairs the induction of LTP and spatial learning (Zhou et al., 2007).”

“CA1 region-specific knock-out of the NR1 subunit of the NMDAR abolishes LTP, in addition to impairing spatial memory (Tsien et al., 1996).”

“thermore, the enzymatic activity of these kinases can be regulated by the reduction and oxidation of the cysteine residues located in their structure (Raynaud et al., 1997; Griendling et al., 2000; Knapp and Klann, 2000).”

“, 1997; Billard and Rouaud, 2007), suggesting that age-related LTP and memory deficits are due to a decrease in the NMDARmediated component of synaptic transmission (Foster, 1999, 2007; Rosenzweig and Barnes, 2003), also referred to here as “NMDAR hypofunction.”

“Similarly, bath application of the CaMK inhibitor KN-62 (10 M, 45 min) (Tokumitsu et al., 1990), before and during the application of DTT, blocked (97.9 7.98%, n 5) the DTT-mediated increase in NMDAR-fEPSP in aged animals (Fig.”

“CaMKII contributes to DTT-mediated enhancement of NMDAR responses in aged animals NMDAR function is controlled by several intracellular kinases (Ben-Ari et al., 1992; Westphal et al., 1999; Li et al., 2001).”

“Furthermore, phosphatase activity decreases NMDAR function (Lieberman and Mody, 1994; Wang et al., 1994).”

“The redox state of the extracellular cysteine residues of the NMDARs have been implicated in regulating the NMDAR function in cell cultures and neonatal animals (Aizenman et al., 1989, 1990; Bernard et al., 1997; Choi and Lipton, 2000; Choi et al., 2001).”

“…and in tissue from neonates suggests that redox state is an important determinant of NMDAR function (Aizenman et al., 1989, 1990; Bernard et al., 1997; Choi and Lipton, 2000; Choi et al., 2001), possibly through oxidation of extracellular cysteine residues on the NMDAR (Lipton et al., 2002).”

“Indeed, the maintenance of the intracellular redox state is crucial for appropriate NMDA receptor function at hippocampal synapses during LTP processes (Bodhinathan et al., 2010), and also for neurogenic function within the SGZ of the hippocampus (Huang et al., 2012a).”

“Modulation of intracellular redox state has also been shown to alter the NMDA responses at hippocampal synapses in the aged, but not young rats (Bodhinathan et al., 2010), which may be relevant for the study of age-dependent cognitive decline.”