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The Journal of Neuroscience, March 14, 2007, 27(11):2846-2857; doi:10.1523/JNEUROSCI.0116-07.2007

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

Yitao Liu,¹ Tak Pan Wong,¹ Michelle Aarts,² Amanda Rooyakkers,¹ Lidong Liu,¹ Ted Weita Lai,¹ Dong Chuan Wu,¹ Jie Lu,¹ Michael Tymianski,² Ann Marie Craig,¹ and Yu Tian Wang¹

¹Brain Research Centre, Vancouver Coastal Health Research Institute and University of British Columbia, Vancouver, British Columbia, Canada V6T 2B5, and ²Toronto Western Hospital Research Institute, Toronto, Ontario, Canada M5T 2S8

Correspondence should be addressed to Dr. Yu Tian Wang, Brain Research Centre, University of British Columbia Hospital, 2211 Wesbrook Mall, Vancouver, British Columbia, Canada V6T 2B5. Email: ytwang{at}interchange.ubc.ca

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.

Key words: stroke; focal ischemia; NMDA receptor; glycine; neuroprotection; rat

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Received Sept. 18, 2006; revised Jan. 8, 2007; accepted Feb. 4, 2007.

Correspondence should be addressed to Dr. Yu Tian Wang, Brain Research Centre, University of British Columbia Hospital, 2211 Wesbrook Mall, Vancouver, British Columbia, Canada V6T 2B5. Email: ytwang{at}interchange.ubc.ca

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