Studies of the development of brain barrier systems to lipid insoluble molecules in fetal sheep.

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Abstract
The development of the blood-brain and blood-CSF barriers to lipid insoluble substances of different molecular radii was studied in fetal sheep, early (60 days) and late (125 days) in gestation, using labeled erythritol (C14), sucrose (3H or 14C), inulin (3H or 14C) and albumin (125I), or albumin and IgG detected by immunoassay. Morphological studies of fetal brain and choroid plexus at the same gestational stages were carried out using thin section EM and the freeze fracture techniques. Penetration of markers into CSF was substantially greater at 60 days than at 125 days, but at both ages the steady-state level achieved appeared to be related to molecular size. A simple model describing penetration from blood into CSF at 60 days is proposed. It involves the assumption that CSF and brain extracellular fluid are effectively separate compartments; morphological and permeability data which supports this assumption is presented. The data for CSF at 60 days are consistent with the suggestion that the markers penetrate into CSF by diffusion and are not restricted by small pores in the interface between blood and CSF. The reduction in penetration which occurred by 125 days for all markers except erythritol appears to be accounted for by an increase in the sink effect and a decrease in the effective surface area for exchange between blood and CSF. Intercellular tight junctions of both cerebral endothelial cells and choroid plexus epithelial cells were well formed at 60 days gestation. There was no change in junctional characteristics previously thought to correlate with transepithelial permeability (tight junction depth and strand number) between the 2 ages studied, although there were marked changes in permeability. In the fetus much of the penetration of lipid insoluble non-polar substances across the blood-CSF barrier and perhaps across the blood-brain barrier occurs via a transcellular route consisting of a system of tubulo-cisternal endoplasmic reticulum. Penetration via the choroid plexus appears to be the dominant route for penetration from blood into CSF in the 60 day fetus.