Neuronal and Glial Expression of GluN2C and GluN2D NMDA Receptor Subunit mRNA in Different Regions of the Mouse Forebrain

N-methyl-D-aspartate (NMDA) receptors are a subtype of glutamate receptors that are widely expressed in the brain, where they mediate critical functions. While the actions of the predominate GluN2 NMDAR subunits, GluN2A and GluN2B are relatively well understood, the function of GluN2C and GluN2D in the telencephalon is largely unknown. To better understand the possible role of GluN2C and GluN2D subunits, we used fluorescence in situ hybridization together with multiple cell markers to define the distribution and type of cells expressing GluN2C and GluN2D mRNA. Also, a GluN2C-KO mouse was used as a negative control. GluN2C mRNA expression was only found in non-neuronal cells in the telencephalon (except for globus pallidus). In addition, a significant fraction of astrocytes expressed GluN2C mRNA. In contrast to GluN2C, GluN2D subunit mRNA colocalized with neuronal and not astrocyte markers in the telencephalon. In the thalamus, GluN2C and GluN2D mRNA showed region-specific distributions as previously reported, and both subunits mRNA were expressed in neurons. Consistent with these findings, cellular colocalization of GluN2C and GluN2D mRNA was found in the thalamus but not in the telencephalon, except for the globus pallidus. Furthermore, the type of GluN2D-expressing neurons was examined by colocalization with GAD67 mRNA and found to be GAD67-positive interneurons. Among GluN2 NMDA receptor subunits, GluN2C expression was selective to astrocytes in the telencephalon. This specific pattern of distribution could indicate a distinct function. Since glutamate and intracellular Ca2+ signaling are linked to glucose uptake in astrocytes, a potential role of GluN2C-containing NMDA receptors in regulating astrocytic glucose uptake was investigated using autoradioactive analysis. Compared to wild-type mice, GluN2C-KO mice were found to have less glucose uptake after ketamine-induced neuronal activation. These data suggest that GluN2C play a role in stimulating glucose transport into astrocytes. Taken together, defining the cell-type distribution of GluN2C and GluN2D helps in understanding their functions in the brain and discovering therapeutic targets to treat neurological diseases and psychiatric disorders