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Cereb Cortex. 2015 Feb;25(2):482-95. doi: 10.1093/cercor/bht246. Epub 2013 Sep 17.

Developmental expression of N-methyl-D-aspartate (NMDA) receptor subunits in human white and gray matter: potential mechanism of increased vulnerability in the immature brain.

Author information

1
Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA Harvard Medical School, Boston, MA 02115, USA.
2
Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA Harvard Medical School, Boston, MA 02115, USA Current address: Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
3
Harvard Medical School, Boston, MA 02115, USA Clinical Research Center.
4
Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA Harvard Medical School, Boston, MA 02115, USA Department of Pathology (Neuropathology), Boston Children's Hospital, Boston, MA 02115, USA.
5
Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA Harvard Medical School, Boston, MA 02115, USA Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA Current address: Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Abstract

The pathophysiology of perinatal brain injury is multifactorial and involves hypoxia-ischemia (HI) and inflammation. N-methyl-d-aspartate receptors (NMDAR) are present on neurons and glia in immature rodents, and NMDAR antagonists are protective in HI models. To enhance clinical translation of rodent data, we examined protein expression of 6 NMDAR subunits in postmortem human brains without injury from 20 postconceptional weeks through adulthood and in cases of periventricular leukomalacia (PVL). We hypothesized that the developing brain is intrinsically vulnerable to excitotoxicity via maturation-specific NMDAR levels and subunit composition. In normal white matter, NR1 and NR2B levels were highest in the preterm period compared with adult. In gray matter, NR2A and NR3A expression were highest near term. NR2A was significantly elevated in PVL white matter, with reduced NR1 and NR3A in gray matter compared with uninjured controls. These data suggest increased NMDAR-mediated vulnerability during early brain development due to an overall upregulation of individual receptors subunits, in particular, the presence of highly calcium permeable NR2B-containing and magnesium-insensitive NR3A NMDARs. These data improve understanding of molecular diversity and heterogeneity of NMDAR subunit expression in human brain development and supports an intrinsic prenatal vulnerability to glutamate-mediated injury; validating NMDAR subunit-specific targeted therapies for PVL.

KEYWORDS:

N-methyl-d-aspartate; excitotoxicity; glutamate; hypoxia-ischemia; periventricular leukomalacia

PMID:
24046081
PMCID:
PMC4303802
DOI:
10.1093/cercor/bht246
[Indexed for MEDLINE]
Free PMC Article
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