Neuronal viability is controlled by a functional relation between synaptic and extrasynaptic NMDA receptors

Abstract

N-methyl-D-aspartate receptors (NMDARs) are critical for synaptic plasticity that underlies learning and memory. But, they have also been described as a common source of neuronal damage during stroke and neurodegenerative diseases. Several studies have suggested that cellular location of NMDARs (synaptic or extrasynaptic) is a key parameter controlling their effect on neuronal viability. The aim of the study was to understand the relation between these two pools of receptors and to determine their implication in both beneficial and/or deleterious events related to NMDAR activation. We demonstrated that selective extrasynaptic NMDAR activation, as well as NMDA bath application, does not activate extracellular signal-regulated kinase (ERK) pathways, but induces mitochondrial membrane potential breakdown and triggers cell body and dendrite damages, whereas synaptic NMDAR activation is innocuous and induces a sustained ERK activation. The functional dichotomy between these two NMDAR pools is tightly controlled by glutamate uptake systems. Finally, we demonstrated that the only clinically approved NMDAR antagonist, memantine, preferentially antagonizes extrasynaptic NMDARs. Together, these results suggest that extrasynaptic NMDAR activation contributes to excitotoxicity and that a selective targeting of the extrasynaptic NMDARs represents a promising therapeutic strategy for brain injuries.

Opposing Roles of Synaptic and Extrasynaptic NMDA Receptor Signaling in Cocultured Striatal and Cortical Neurons

“…Previous studies in cortical and hippocampal cultures suggest that low memantine concentrations preferentially block extrasynaptic NMDAR activity, whereas higher concentrations also block synaptic transmission (Chen and Lipton, 2006;Léveillé et al, 2008;Xia et al, 2010). Treatment with low concentrations of memantine protects against NMDA-induced toxicity in vitro Papadia et al, 2008;Gouix et al, 2009;Bordji et al, 2010), as well as neurotoxicity and learning deficits in chemical lesion models (Misztal et al, 1996;Lee et al, 2006) and neurodegenerative disease models (Okamoto et al, 2009;Martinez-Coria et al, 2010;.…”

“…Calcium influx through NMDARs initiates signaling for synaptic plasticity, gene transcription, and survival (Dingledine et al, 1999;Hardingham et al, 2002;Bading, 2003, 2010;Léveillé et al, 2008Léveillé et al, , 2010. In contrast, excessive Ca 2ϩ entry through NMDARs causes glutamate excitotoxicity (Choi, 1987;Tymianski et al, 1993;Arundine et al, 2003;Léveillé et al, 2010).…”

“…Regardless of subunit composition, synaptic NMDARs activate cellular antioxidant defenses (Papadia et al, 2005), initiate signaling through extracellular signal-related kinase (ERK) (Ivanov et al, 2006), affect histone acetylation (Wittmann et al, 2009), suppress death pathways (Léveillé et al, 2010), and phosphorylate cAMP response element binding protein (CREB) (Hardingham et al, 2002;Léveillé et al, 2008), a transcription factor that regulates gene expression important for survival and plasticity (Lonze and Ginty, 2002). In contrast, extrasynaptic NMDARs shut off cell survival pathways (Hardingham et al, 2002), induce mitochondrial dysfunction (Gouix et al, 2009), and activate pro-death molecules (Léveillé et al, 2010).…”

Dysfunctional synapse in Alzheimer's disease – A focus on NMDA receptors

“…expression (Hardingham et al, 2002), whereas activation of extrasynaptic NMDARs activated a general and dominant CREB shut-off pathway (Kaufman et al, 2012;Hardingham et al, 2002); this effect could be prevented by the use of memantine (Kaufman et al, 2012), commonly used as AD treatment, and which preferentially blocks extrasynaptic NMDARs at therapeutic concentration (Leveille et al, 2008;Xia et al, 2010). These data suggest that extrasynaptic NMDARs activation contributes to excitotoxicity.…”

“…The extracellular signal-regulated kinases (ERK), which promote a signaling cascade important for neuronal plasticity and survival, are regulated, in part, through NMDARs activation. Thus, the synaptic pool of NMDARs activates ERK, promoting cell survival (Ivanov et al, 2006;Leveille et al, 2008), whereas the extrasynaptic pool of NMDARs triggers mitochondrial membrane potential breakdown, as well as cell body and dendritic damage (Leveille et al, 2008), inducing a signaling pathway that inactivates ERK (Ivanov et al, 2006). Interestingly, the simultaneous activation of synaptic and extrasynaptic NMDARs induces ERK activation, weaker than those mediated by synaptic NMDARs alone (Ivanov et al, 2006).…”