Corticotropin-Releasing Hormone Receptor-1 in Cerebral Microvessels Changes during Development and Influences Urocortin Transport across the Blood-Brain Barrier

Abstract

In this study we tested the hypothesis that receptor-mediated transport of urocortin across the blood-brain barrier (BBB) undergoes developmental changes. Urocortin is a peptide produced by both selective brain regions and peripheral organs, and it is involved in feeding, memory, mood, cardiovascular functions, and immune regulation. In BBB studies with multiple-time regression analysis, we found that neonatal mice had a significant influx of (125)I-urocortin. By contrast, adult mice did not transport urocortin across the BBB. Quantitative RT-PCR showed that corticotropin-releasing hormone receptor (CRHR)-1 was developmentally regulated in enriched cerebral microvessels as well as hypothalamus, being significantly higher in neonatal than adult mice. This change was less dramatic in agouti viable yellow mice, a strain that develops adult-onset obesity. The level of expression of CRHR1 mRNA was 33-fold higher in the microvessels than in hypothalamic homogenates. The mRNA for CRHR2 was less abundant in both regions and less prone to changes with development or the agouti viable yellow mutation. Supported by previous findings of receptor-mediated endocytosis of urocortin, these results suggest that permeation of urocortin across the BBB is dependent on the level of CRHR1 expression in cerebral microvessels. These novel findings of differential regulation of CRH receptor subtypes help elucidate developmental processes in the brain, particularly for the urocortin system.