Abstract
Post-ischemic activation of NMDA receptors (NMDARs) has been linked to NMDAR subunit-specific signaling that mediates pro-survival or pro-death activity. Although extensive studies have been performed to characterize the role of GluN2A and GluN2B following ischemia, there is less understanding regarding the regulation of GluN2C. Here, we show that GluN2C expression is increased in acute hippocampal slices in response to ischemia. Strikingly, GluN2C knockout mice, following global cerebral ischemia, exhibit greater neuronal death in the CA1 area of the hippocampus and reduced spatial working memory compared to wild-type mice. Moreover, we find that GluN2C-expressing hippocampal neurons show marked resistance to NMDA-induced toxicity and reduced calcium influx. Using both in vivo and in vitro experimental models of ischemia, we demonstrate a neuroprotective role of GluN2C, suggesting a mechanism by which GluN2C is upregulated to promote neuronal survival following ischemia. These results may provide insights into development of NMDAR subunit-specific therapeutic strategies to protect neurons from excitotoxicity.
Highlights
The GluN2C subunit confers unique properties on the NMDA receptors (NMDARs) ion channels including low conductance openings and low sensitivity to magnesium[10,11]
In an in vitro acute hippocampal slice model of cerebral ischemia, it has previously been shown that GluN2C mRNA levels increase following 4 minute oxygen-glucose deprivation (OGD) in the hippocampus, whereas GluN2A and GluN2B levels remain stable and GluN2D is undetectable[7,8]
Consistent with previous published reports, OGD significantly increased GluN2C mRNA levels, whereas there were no significant changes in GluN2A and GluN2B mRNA levels (Fig. 1a)
Summary
The GluN2C subunit confers unique properties on the NMDAR ion channels including low conductance openings and low sensitivity to magnesium[10,11]. This is true for both GluN1/GluN2C receptors expressed in heterologous cells and native NMDARs in the cerebellum. Our findings reveal a potential homeostatic mechanism that regulates NMDAR subunit composition in response to increased calcium influx. Through such a mechanism, the intracellular calcium level and NMDAR signaling can be maintained at equilibrium
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