NMDA Receptor Subunits Have Differential Roles in Mediating Excitotoxic Neuronal Death Both In Vitro and In Vivo

By Yitao Liu, T. Wong, M. Aarts, Amanda Rooyakkers, Lidong Liu, T. Lai, D. Wu, Jie Lu, M. Tymianski, Ann Marie Craig and 1 more. Journal of Neuroscience, 2007

800 citations recorded by the source corpus.

Well-documented experimental evidence from both in vitro and in vivo models of stroke strongly supports the critical involvement of NMDA receptor-mediated excitotoxicity in neuronal damage after stroke. Despite this, the results of clinical trials testing NMDA receptor antagonists as neuroprotectants after stroke and brain trauma have been discouraging. Here, we report that in mature cortical cultures, activation of either synaptic or extrasynaptic NR2B-containing NMDA receptors results in excitotoxicity, increasing neuronal apoptosis. In contrast, activation of either synaptic or extrasynaptic NR2A-containing NMDA receptors promotes neuronal survival and exerts a neuroprotective action against both NMDA receptor-mediated and non-NMDA receptor-mediated neuronal damage. A similar opposing action of NR2B and NR2A in mediating cell death and cell survival was also observed in an in vivo rat model of focal ischemic stroke. Moreover, we found that blocking NR2B-mediated cell death was effective in reducing infarct volume only when the receptor antagonist was given before the onset of stroke and not 4.5 h after stroke. In great contrast, activation of NR2A-mediated cell survival signaling with administration of either glycine alone or in the presence of NR2B antagonist significantly attenuated ischemic brain damage even when delivered 4.5 h after stroke onset. Together, the present work provides a molecular basis for the dual roles of NMDA receptors in promoting neuronal survival and mediating neuronal damage and suggests that selective enhancement of NR2A-containing NMDA receptor activation with glycine may constitute a promising therapy for stroke.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology, Neurology

View Paper: https://www.semanticscholar.org/paper/ddfa06031169565e3f6194ed3e1f617bb9b72196

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In Cellular and Molecular Neuroscience

1. D. Selkoe
2. Nina E. Shepardson
3. G. Shankar
4. Shaomin Li
5. Hilmar Bading
6. G. Hardingham
7. L. Mucke
8. D. Holtzman

In Molecular Biology

1. D. Selkoe
2. G. Shankar
3. Hilmar Bading
4. G. Hardingham
5. David Watson
6. Sokratis G. Papageorgiou
7. K. Yiannopoulou

In Neurology

1. D. Selkoe

Citations in the corpus

• Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders (2010, positive): “Indeed, GluN2B- or GluN2A-containing NMDARs have been proposed to promote neuronal death and neuronal survival, respectivel”
• Soluble Aβ oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors (2011, background): “Accordingly, NR2Bselective antagonists effectively prevent glutamate-induced excitotoxicity in ischemia (Hardingham et al., 2002; Liu et al., 2007) and rescue A -inhibited LTP (Hu et al.”