Developmental regulation of AMPA receptor subunit expression in forebrain and relationship to regional susceptibility to hypoxic/ischemic injury: Part II. Human cerebral white matter and cortex

This report is the second of a two-part evaluation of developmental differences in α–amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor subunit expression in cell populations within white matter and cortex. In Part I, we report that in rat, developmental expression of Ca2+ permeable (GluR2-lacking) AMPARs correlated at the regional and cellular level with increased susceptibility to hypoxia/ischemia (H/I), suggesting an age-specific role of these receptors in the pathogenesis of brain injury. Part II examines the regional and cellular progression of AMPAR subunits in human white matter and cortex from midgestation through early childhood. Similar to the rodent, there is a direct correlation between selective vulnerability to H/I and expression of GluR2-lacking AMPARs in human brain. In midgestational cases aged 20-24 postconceptional weeks (PCW) and in premature infants (25-37 PCW), we found that radial glia, premyelinating oligodendrocytes and subplate neurons transiently expressed GluR2-lacking AMPARs. Notably, prematurity represents a developmental window of selective vulnerability for white matter injury, such as periventricular leukomalacia (PVL). During term (38-42 PCW) and post-term neonatal (43-46 PCW) periods, age windows characterized by increased susceptibility to cortical injury and seizures, GluR2 expression was low in the neocortex, specifically on cortical pyramidal and non-pyramidal neurons. This study indicates that Ca2+ permeable AMPAR blockade may represent an age-specific therapeutic strategy for potential use in humans. Furthermore, these data help validate specific rodent maturational stages as appropriate models for evaluation of H/I pathophysiology.