A deficiency of the GluN2C subunit of the N-methyl-D-aspartate receptor is neuroprotective in a mouse model of ischemic stroke

Roles of GluN2C in cerebral ischemia: GluN2C expressed in different cell types plays different role in ischemic damage

“…Additionally, GluN2C was expressed in the oligodendrocyte processes in the white matter and may be one of the most abundant NMDA receptors subunits (Burzomato, Frugier, Perez‐Otano, Kittler, & Attwell, ; Karadottir, Cavelier, Bergersen, & Attwell, ; Salter & Fern, ). The GluN2C subunits in the above brain regions may be involved in the processes of circadian (Brancaccio, Patton, Chesham, Maywood, & Hastings, ), tuberous sclerosis complex‐ or focal cortical dysplasia‐induced epilepsy (Lozovaya et al, ), depression (Karolewicz, Stockmeier, & Ordway, ), fear acquisition (Hillman, Gupta, Stairs, Buonanno, & Dravid, ; Ogden, Khatri, Traynelis, & Heldt, ), and cerebral ischemia (Chung et al, ; Doyle et al, ; Holmes et al, ; Kadotani et al, ) (Table ).…”

“…Early research showed that at 24 hr after permanent MCAO in mice, the infarct volumes of GluN2C knockout mice were significantly smaller (50%–60% reduction) than those in the wild‐type mice (Kadotani et al, ). Recently, Holmes et al found no significant differences in both infarct size and neurological scores between wild‐type and GluN2C knockout/nβ‐galactosidase knock‐in mice at 24 hr post‐transient MCAO; however, the neuronal area in the penumbra of GluN2C knockout mice was significantly larger than the neuronal size in the WT penumbra, and the pyknotic nucleation in knockout mice was significantly decreased (Holmes et al, ). Moreover, at 72 hr post‐transient MCAO, GluN2C knockout mice showed significantly lower average of neurological scores, weight loss, and brain edema (Holmes et al, ).…”

“…Recently, Holmes et al found no significant differences in both infarct size and neurological scores between wild‐type and GluN2C knockout/nβ‐galactosidase knock‐in mice at 24 hr post‐transient MCAO; however, the neuronal area in the penumbra of GluN2C knockout mice was significantly larger than the neuronal size in the WT penumbra, and the pyknotic nucleation in knockout mice was significantly decreased (Holmes et al, ). Moreover, at 72 hr post‐transient MCAO, GluN2C knockout mice showed significantly lower average of neurological scores, weight loss, and brain edema (Holmes et al, ). Doyle et al reported that 2 hr pretreatment with GluN2C/D‐specific antagonist QNZ‐46 prevented ischemia‐ or OGD‐induced myelin injury, such as increased myelin thickness, extensive myelin decompaction, and bubbling (Doyle et al, ).…”

“…injection of QNZ‐46 2 hr before ischemia greatly reduced lesion volume, significantly increased external capsule axon integrity, and improved the performance in behavioral tests compared to vehicle‐treated controls at 24 hr post‐transient MCAO (Doyle et al, ). The possible mechanism for the pro‐death effect of GluN2C may be that indirectly enhancing GluN2B function via promoting the phosphorylation of GluN2B at Tyr1336 (Holmes et al, ), decreasing nuclear localization of activated cyclic‐AMP response element‐binding protein (Holmes et al, ), and mediating ischemia‐induced release of axonal vesicular glutamate into the peri‐axonal space under the myelin sheath (Doyle et al, ).…”

“…A typical NMDA receptor constitutes two GluN1 and two GluN2 subunits. Recently, several studies observed opposite results on the roles of GluN2C in cerebral ischemia (Chen & Roche, ; Chung et al, ; Doyle et al, ; Holmes, Zhou, Donahue, Balsara, & Castellino, ; Kadotani, Namura, Katsuura, Terashima, & Kikuchi, ). The purpose of this minireview is to explain the above contradictory results.…”