Neonatal rats survive and avoid
brain injury during periods of
anoxia 25 times longer than adults. We hypothesized that
oxygen activates and
hypoxia suppresses
NMDA receptor (NMDAR) responses in neonatal rat neurons, explaining the innate
hypoxia tolerance of these cells. In CA1 neurons isolated from neonatal rat hippocampus (mean postnatal age [P] 5.8 days),
hypoxia (PO(2) 10 mm Hg) reduced
NMDA receptor-channel open-time percentage and
NMDA-induced increase in [Ca(2+)](i) (
NMDA DeltaCa(2+)) by 38 and 68% (P<0.01), respectively. In P20 neurons the reductions were not significant. In P3-10 CA1 neurons within intact hippocampal slices,
hypoxia reduced
NMDA DeltaCa(2+) by 52% (P=0.002) and decreased
NMDA-induced death by 45% (P=0.004).
Phalloidin, a microtubule stabilizer, prevented
hypoxia-induced inhibition of
NMDA DeltaCa(2+) in P3-10 neurons. To test whether NMDARs prevalent in neonates (NR1 plus NR2B or NR2D subunits) are inhibited by
hypoxia compared with those in mature neurons (NR2A and NR2C), we expressed these receptors in Xenopus oocytes. Compared with responses in 21% O(2),
hypoxia (PO(2) 17 mm Hg) reduced currents from neonatal type NR1/NR2D receptors by 25%, increased currents from NR1/NR2C by 18%, and had no effect on NR1/NR2A or NR1/NR2B. Modulation of NMDARs by
hypoxia may play an important role in the
hypoxia tolerance of the mammalian neonate. In addition,
oxygen sensing by NMDARs could play a significant role in postnatal brain development.