NMDA receptor-mediated excitotoxicity depends on the coactivation of synaptic and extrasynaptic receptors

Abstract

N-methyl-𝒟-aspartate receptors (NMDAR) overactivation is linked to neurodegeneration. The current prevailing theory suggests that synaptic and extrasynaptic NMDAR (syn- and ex-NMDAR) impose counteracting effects on cell fate, and neuronal cell death is mainly mediated by the activation of ex-NMDAR. However, several lines of evidence implicate the limitation of this theory. Here, we demonstrate that activation of NMDAR bi-directionally regulated cell fate through stimulating pro-survival or pro-death signaling. While low-dose NMDA preferentially activated syn-NMDAR and stimulated the extracellular signal-regulated kinase ½–cAMP responsive element-binding protein–brain-derived neurotrophic factor pro-survival signaling, higher doses progressively activated increasing amount of ex-NMDAR along with syn-NMDAR and triggered cell death program. Interestingly, the activation of syn- or ex-NMDAR alone did not cause measurable cell death. Consistently, activation of syn- or ex-NMDAR alone stimulated pro-survival but not pro-death signaling. Next, we found that memantine, which was previously identified as an ex-NMDAR blocker, inhibited intracellular signaling mediated by syn- or ex-NMDAR. Simultaneous blockade of syn- and ex-NMDAR by memantine dose-dependently attenuated NMDAR-mediated death. Moreover, long- but not short-term treatment with high-dose NMDA or oxygen–glucose deprivation triggered cell death and suppressed pro-survival signaling. These data implicate that activation of syn- or ex-NMDAR alone is not neurotoxic. The degree of excitotoxicity depends on the magnitude and duration of syn- and ex-NMDAR coactivation. Finally, genome-wide examination demonstrated that the activation of syn- and ex-NMDAR lead to significant overlapping rather than counteracting transcriptional responses.

Involvement of the GluN2A and GluN2B Subunits in Synaptic and Extrasynaptic N-methyl-d-aspartate Receptor Function and Neuronal Excitotoxicity

“…Specifically, we demonstrated that the prosurvival CREB (cAMP response element-binding protein) signaling is up-regulated by the activation of either syn-or ex-NMDAR. Coactivation of syn-and ex-NMDAR triggers cell death and dampens CREB signaling (17). Here we demonstrate that both GluN2A and GluN2B are involved in syn-as well as ex-NMDAR function.…”

“…Cortices were obtained from postnatal day 0 Sprague-Dawley rats, dissociated, and used for the primary culture as described in our previous study (17).…”

“…Our previous study (17) shows how NMDAR bidirectionally regulates cell survival and death. Specifically, we demonstrated that the prosurvival CREB (cAMP response element-binding protein) signaling is up-regulated by the activation of either syn-or ex-NMDAR.…”

Organization, control and function of extrasynaptic NMDA receptors

“…But, here again, this idea is facing contradictory results (table 1). For example, even though they followed the protocols previously published in the field [15], Zhou et al [116] were recently unable to observe any preferential involvement of GluN2A-or GluN2B-NMDARs in excitotoxicity. By contrast, the group of Giles Hardingham demonstrates in a recent study that the CTD of NMDARs, rather than the channel's properties, is crucial in determining how they influence excitotoxicity [128].…”

Current Stage and Future Perspective of Stem Cell Therapy in Ischemic Stroke

“…Despite of tremendous research efforts made to discover new neuroprotective strategies to limit acute injury to neuronal cells in ischemic area. Neuroprotection can be achieved by reducing the release of excitatory neurotransmitters in the ischemic area in order to enhance the neuronal survival [11,12]. However, several studies have reported neuroprotective strategies that are successful in animal stroke model, but these strategies failed in randomized placebocontrolled human studies.…”