title: Neuroprotection Mediated through GluN2C-Containing N-methyl-D-aspartate (NMDA) Receptors Following Ischemia.
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.
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA.|Department of Neurology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA.
authors.forename: Connie
authors.initials: C
authors.lastname: Chung
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA.|Department of Neurology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Marson
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA.|Department of Neurology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA.
authors.forename: Quan-Guang
authors.initials: QG
authors.lastname: Zhang
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA.|Department of Neurology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA.
authors.forename: Jimok
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA.|Department of Neurology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA.
authors.forename: Wei-Hua
authors.initials: WH
authors.lastname: Wu
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA.|Department of Neurology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA.
authors.forename: Darrell W
authors.initials: DW
authors.lastname: Brann
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA.|Department of Neurology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA.
authors.forename: Bo-Shiun
authors.initials: BS
authors.lastname: Chen
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020013:Calcium Signaling; D016923:Cell Death; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D000066829:Neuroprotection; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C432823:NR2C NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate