Abstract 2333: The Role Of Extrasynaptic NMDA Receptor In Mediating Neuronal Survival- And Death-related Signaling

Abstract

The N-methyl-D-aspartate receptors (NMDARs) play an important role in synaptic plasticity and excitotoxicity. Physiological activation of NMDARs is associated with synaptic plasticity and neuronal survival, whereas excessive activation of NMDARs contributes to neuronal death. Previous studies suggest that activation of synaptic NMDARs promotes neuronal survival. In contrast, activation of extrasynaptic NMDARs results in neuronal cell death. However, the precise roles of NMDARs at different subcellular locations are not completely understood. Here we present new evidence that activation of extrasynaptic NMDARs alone does not cause neuronal death; whereas co-activation of extrasynaptic and synaptic NMDARS does. Specifically, after blocking synaptic NMDARs with MK801 and bicuculline, higher concentration of NMDA or glutamate activated extrasynaptic NMDARs, but did not lead any significant neuronal death in DIV14 or much older cultures. Consistently, 75 min oxygen glucose deprivation, a cellular ischemic stroke model, did no cause any obvious neuronal death after blockade of synaptic NMDARs. In contrast, without pretreatment of bicuculline and MK801, oxygen glucose deprivation induced 73.6 % cell death. Additionally, we obtained the same conclusion with another protocol, a combination of low dose of NMDA (15 μM, supposed to activate only synaptic NMDARs) and MK801, to block synaptic NMDARs. Further, we show that activation of either synaptic or extrasynaptic NMDARs promoted neuronal survival signaling and did not disturb intracellular calcium homeostasis. However, co-activation of synaptic and extrasynaptic NMDARs led to shut-off of neuronal survival signaling, triggered neuronal death signaling, and disturbed intracellular calcium homeostasis. More importantly, by examining NMDAR-related survival signaling and calcium signaling, we found that activation of extrasynaptic NMDARs requires a higher concentration of ligand, suggesting that extrasynaptic NMDARs have a relative lower ligand affinity compared to synaptic NMDARs. These findings will provide new evidence on the role of extrasynaptic NMDARs, and suggest a new direction for designing neuroprotective drugs to selectively block extrasynaptic NMDARs while leaving synaptic NMDAR functions intact.