Vulnerability of white matter towards antenatal hypoxia is linked to a species-dependent regulation of glutamate receptor subunits.

Abstract

White-matter damage is a leading cause of neurological handicap. Although hypoxia-ischemia and excitotoxicity are major pathogenic factors, a role for genetic influences was suggested recently. Thus, protracted gestational hypoxia was associated with white-matter damage (WMD) in rat pups but not in mouse pups. Indeed, microglial activation and vessel-wall density on postnatal days (P)1 and P10 were found increased in both mouse and rat pups, but cell death, astrogliosis, and myelination were only significantly altered in hypoxic rat pups. We investigated whether this species-related difference was ascribable to effects of antenatal hypoxia on the expression of glutamate receptor subunits by using immunocytochemistry, PCR, and excitotoxic double hit insult. Quantitative PCR in hypoxic mouse pups on P1 showed 2- to 4-fold down-regulation of the AMPA-receptor subunits -1, 2, and -4; of the kainate-receptor subunit GluR7; and of the metabotropic receptor subunits mGluR1, -2, -3, -5, and -7. None of the glutamate-receptor subunits was down-regulated in the hypoxic rat pups. NR2B was the only NMDA-receptor subunit that was down-regulated in hypoxic mice but not in hypoxic rat on P1. Ifenprodil administration to induce functional inhibition of NMDA containing NR2B-subunit receptors prevented hypoxia-induced myelination delay in rat pups. Intracerebral injection of a glutamate agonist produced a larger decrease in ibotenate-induced excitotoxic lesions in hypoxic mouse pups than in normoxic mouse pups. Gestational hypoxia may regulate the expression of specific glutamate-receptor subunits in fetal mice but not in fetal rats. Therefore, genetic factors may influence the susceptibility of rodents to WMD.

• Authors: Romain H Fontaine, Paul Olivier, Véronique Massonneau, Philippe Leroux, Vincent Degos, Sophie Lebon, Vincent El Ghouzzi, Vincent Lelièvre, Pierre Gressens, Olivier Baud
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 105 Issue 43 Pg. 16779-84 (Oct 28 2008) ISSN: 1091-6490 [Electronic] United States
• PMID: 18922769 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Protein Subunits
• Receptors, AMPA
• Receptors, Glutamate
• Receptors, Kainic Acid
• Receptors, Metabotropic Glutamate

Topics

• Animals
• Animals, Newborn
• Female
• Gene Expression Regulation
• Genetic Predisposition to Disease
• Hypoxia (etiology, genetics)
• Mice
• Nerve Fibers, Myelinated (pathology)
• Pregnancy
• Protein Subunits (genetics)
• Rats
• Receptors, AMPA (genetics)
• Receptors, Glutamate (genetics)
• Receptors, Kainic Acid (genetics)
• Receptors, Metabotropic Glutamate (genetics)
• Species Specificity