Hypoxia associated NMDA receptor 2 subunit composition: developmental comparison between the hypoxia-tolerant subterranean mole-rat, Spalax, and the hypoxia-sensitive rat

Vertebrate brains are sensitive to oxygen depletion, which may lead to cell death. Hypoxia sensitivity originates from the high intrinsic rate of ATP consumption of brain tissue, accompanied by the release of glutamate, leading to the opening of ionotropic glutamate receptors, such as N-methyl-D-aspartate (NMDA) receptors (NMDARs). The relative expression levels of the four NMDAR-2 (NR2) subunits change during mammalian development with higher levels of units NR2B and NR2D observed during early development and correlated with hypoxic tolerance during embryonic and neonatal stages of development. Higher levels of NR2D are also abundant in brains of hypoxia tolerant species such as the crucian carp. The subterranean mole-rat, Spalax spends its life underground in sealed burrows and has developed a wide range of adaptations to this special niche including hypoxia-tolerance. In this study, we compared the in vivo mRNA expression of NR2 subunits in the brains of embryonic, neonatal and adult Spalax and rat. Our results demonstrate that under normoxic conditions, mRNA levels of NR2D are higher in Spalax than in rat at all developmental stages studied and are similar to levels in neonatal rat and in other hypoxia/anoxia tolerant species. Furthermore, under hypoxia Spalax NR2D mRNA levels increase while no response was observed in rat. Similarly, hypoxia induces an increase in mRNA levels of Spalax NR2A, claimed to promote neuronal survival. We suggest that indeed the proportional combinations of NMDAR-2 subunits contribute to the ability of the Spalax brain to cope with hypoxic environments.