Subunit-specific effects of NMDA receptor signaling: Implications for stroke

Abstract

Ischemic brain damage is largely due to excitotoxicity triggered by over-activation of N-methyl-D-aspartate receptors (NMDARs). However, to date none of the NMDAR antagonists have shown therapeutic benefit in clinical trials for stroke. The reasons for this failure are not fully understood. We show here that, in stroke models in vitro and in vivo, blockade of the NR2A-containing NMDARs does not confer neuroprotection, and instead, it results in exacerbation of neuronal death. In contrast, selectively blocking the NR2B-containing NMDAR subtype still attenuates ischemic brain injury. To unravel the mechanisms underlying these opposing effects, we examined the individual role of these two NMDAR subtypes in neuronal fate in mature cortical cultures and found that the NR2A-containing NMDARs mediate neuronal survival while the NR2B-containing counterparts are coupled to neuronal apoptosis. We also showed that NR2A- and NR2B-containing NMDARs co-localize at synaptic (2A:2B2:1) and extrasynaptic (2A:2B1:3) sites. The effects of these two NMDAR subtypes on neuronal fate are dependent on the subunit composition rather than the subcellular location. These findings not only provide a molecular basis for why NMDAR antagonists were inefficacious in treating stroke, but suggest that the conventional conception about treatment of ischemic brain damage with NMDAR antagonists may have to be renovated. We propose that a promising strategy for stroke treatment should combine functional enhancement of the NR2A-containing NMDARs with selective suppression of the NR2B-containing counterparts.