RT Journal Article
SR Electronic
T1 NMDA Receptor Subunits Have Differential Roles in Mediating Excitotoxic Neuronal Death Both <em>In Vitro</em> and <em>In Vivo</em>
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 2846
OP 2857
DO 10.1523/JNEUROSCI.0116-07.2007
VO 27
IS 11
A1 Yitao Liu
A1 Tak Pan Wong
A1 Michelle Aarts
A1 Amanda Rooyakkers
A1 Lidong Liu
A1 Ted Weita Lai
A1 Dong Chuan Wu
A1 Jie Lu
A1 Michael Tymianski
A1 Ann Marie Craig
A1 Yu Tian Wang
YR 2007
UL http://www.jneurosci.org/content/27/11/2846.abstract
AB 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.