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. 2012 Mar 29:3:46.
doi: 10.3389/fphar.2012.00046. eCollection 2012.

Barrier mechanisms in the developing brain

Norman R Saunders  1 , Shane A Liddelow, Katarzyna M Dziegielewska
Affiliations

Barrier mechanisms in the developing brain

Norman R Saunders et al. Front Pharmacol. .

Abstract

The adult brain functions within a well-controlled stable environment, the properties of which are determined by cellular exchange mechanisms superimposed on the diffusion restraint provided by tight junctions at interfaces between blood, brain and cerebrospinal fluid (CSF). These interfaces are referred to as "the" blood-brain barrier. It is widely believed that in embryos and newborns, this barrier is immature or "leaky," rendering the developing brain more vulnerable to drugs or toxins entering the fetal circulation from the mother. New evidence shows that many adult mechanisms, including functionally effective tight junctions are present in embryonic brain and some transporters are more active during development than in the adult. Additionally, some mechanisms present in embryos are not present in adults, e.g., specific transport of plasma proteins across the blood-CSF barrier and embryo-specific intercellular junctions between neuroependymal cells lining the ventricles. However developing cerebral vessels appear to be more fragile than in the adult. Together these properties may render developing brains more vulnerable to drugs, toxins, and pathological conditions, contributing to cerebral damage and later neurological disorders. In addition, after birth loss of protection by efflux transporters in placenta may also render the neonatal brain more vulnerable than in the fetus.

Keywords: blood–CSF barrier; blood–brain barrier; cerebrospinal fluid; endothelial cell transport; epithelial cell transport; fetus; newborn.

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Figures

Figure 1
Figure 1
Embryonic day E16 rat brain stained for endogenous plasma proteins. (A) Low power coronal section. Immunostaining in CSF, choroid plexus, and ventricular zone, also few blood vessels in cortex. (B) Higher power of cortex: immunostaining in mesenchymal tissue outside brain surface and blood vessels (arrows), not in brain parenchyma. (C) Choroid plexus: immunostaining in some epithelial cells (arrowheads) and stroma. (D) Immunostaining in neuroependymal cells and blood vessels, not in brain parenchyma outside neuroependyma. Open arrows: sites of strap junctions. Images reproduced from Saunders and Habgood (2011). Scale bars: (A), 100 μm; (B,D), 25 μm; (C), 50 μm.
Figure 2
Figure 2
Brain barrier interfaces. (A) Blood–cerebrospinal fluid (CSF) barrier: tight junctions between choroid plexus epithelial cells. (B) Blood–brain barrier: tight junctions between endothelial cells. (C) CSF–brain barrier only present in embryos and fetuses: strap junctions between neuroependymal cells. (D) CSF–brain interface in adult: gap junctions between ependymal cells, with free diffusion pathway (Arrowheads and broken lines). (E) Arachnoid barrier. In adult: tight junctions between cells of the inner layer of the arachnoid membrane and between endothelial cells of pial blood vessels. In embryos: additional membrane specializations at the CSF–pial interface (Møllgård et al., 1987). Abbreviations: bv, blood vessel; endo, endothelial cell; epi, epithelial cell; bm, basement membrane; peri, pericyte; astro, astrocyte (astrocytes not yet differentiated in brain when blood vessels first appear; thus they cannot contribute to tight junction formation in early brain development). Black arrowheads: sites of tight junctions; open arrowheads: sites of strap junctions. Redrawn from Saunders et al. (2008).
Figure 3
Figure 3
Light (LM) and electronmicrographs (EM) of early developing brain blood vessels and choroid plexus, illustrating functional effectiveness of tight junctions. (A) (LM) and (B) (EM) of newborn opossum injected intraperitoneally (i.p.) with 3 kDa biotin dextran. Reaction product confined to vessel lumen (A) not passing through tight junctions [(B), arrowhead]. (C) Newborn opossum choroid plexus injected i.p. with 3 kDa biotin dextran which does not pass through tight junction (arrowhead). (D) E15 rat, tracer injected into lateral ventricle. Choroid plexus tight junctions (arrowhead): no passage of tracer between cells. Images: (A,B) from Ek et al. (2006); (C,D) from Ek et al. (2003). Scale bars: (A), 25 μm; (B), 200 nm; (C), 100 nm; (D), 300 nm.
Figure 4
Figure 4
Proposed transepithelial pathway for albumin through choroid plexus epithelial cells. (A) Whole choroid plexus showing single layer of epithelial cells sitting on thick basement membrane (see also Figure 1C). (B) Suggested routes of albumin from plasma into CSF across the choroid plexus epithelium. GYPA/C in endothelial cells may deliver albumin to basement membrane (1) from where it can be taken up into plexus epithelium by GYPA/C or SPARC (2). Albumin may then travel along a SPARC-specific pathway through tubulocisternal endoplasmic reticulum [3, and see (C)] and Golgi (4a), or via a VAMP-mediated pathway in vacuoles, lysosomes, or multivesicular bodies [4b, and see (C)]. On apical surface of plexus epithelium, GYPA/C may be involved in efflux of protein from the cell into CSF (5). In adult, lack of immunoreactivity in endoplasmic reticulum and Golgi and increased expression of gene products for VAMP molecules, suggest that majority of transport occurs via VAMP-mediated vesicular transport (4b). (C) Transmission electron micrograph of ultracryosection from E60 fetal sheep choroid plexus (Balslev et al., 1997b). Immunolabeled human albumin 6 nm particles and sheep albumin 12 nm gold particles are shown to co-localize within the tubulocisternal endoplasmic reticulum. Abbreviations: CPEC, choroid plexus epithelial cell; CSF, cerebrospinal fluid; GYPA, glycophorin A; GYPC, glycophorin C; MVB, multivesicular body; TER, tubulocisternal endoplasmic reticulum. Scale bar: 0.2 μm in (C). Image from Liddelow et al. (2012).
Figure 5
Figure 5
Cellular localization of fetuin and inert biotin dextran (3 kDa) in postnatal (P9) Monodelphis domestica. Light micrograph showing the localization of bovine fetuin (A,B) detected with its antibodies and biotin dextran (C,D) detected with ABC (ABC kit, Vector Laboratories), in coronal sections of lateral ventricular choroid plexus. (A) Twenty-four hours after intraperitoneal injection of bovine fetuin, specific epithelial cells of the plexus (filled arrows) were found containing the protein. (B) Bovine fetuin was injected into the lateral ventricle and left for 10 min. The protein was not detected in any cells of the plexus, or in the lumen of blood vessels in the plexus stroma. Protein can be seen on the CSF side of the epithelial cells, precipitated on the brush border (unfilled arrow). (C) Forty-five minutes after intraperitoneal injection with BDA (3 kDa), the probe can be seen in specific epithelial cells of the choroid plexus (filled arrow), as well as in the blood vessel lumen (arrowhead) and precipitated in the CSF (unfilled arrow). (D) Ten minutes after intraventricular injection with Fluorescein-conjugated BDA (3 kDa), more epithelial cells take up the probe (filled arrows) following CSF injection compared with intraperitoneal injection (C). Penetration of the fluorescent probe between epithelial cells is stopped by the presence of tight junctions (examples highlighted by arrowheads). (E) Uptake of bovine fetuin and BDA (3 kDa) into choroid plexus epithelial cells in P9 Monodelphis following intraperitoneal or intracerebroventricular injection; mean ± SEM, numbers of immunostained cells. P9 Monodelphis injected with fetuin and BDA (3 kDa) intraperitoneally or into one lateral ventricle. *Percentage of all cells counted. n is the number of individual brains used in the study; BDA (3 kDa), biotinylated dextran amine MW 3 kDa. Scale: 50 μm (A–D). From Liddelow et al. (2009) Figure 3 and Table 7.
Figure 6
Figure 6
Diagram of main inward transporters in cerebral endothelial cells. Heavy metals bind to some amino acids and transferrin receptors. Because of vulnerability of developing brain to heavy metals this transport may contribute to fetal or newborn neurotoxicity. Compare Table 2, which shows transporters expressed in endothelial cells from developing brain, including those up-regulated compared to adult. Abbreviations: ala, alanine; cys, cysteine; Fe2+, iron; Glu, glutamate; his, histidine; MCT, monocarboxylate transporter; MeHg, methyl mercury; met, methionine; Mn2+, manganese; Pb2+, lead; pro, proline; trp, tryptophan; Zn2+, zinc.
Figure 7
Figure 7
Diagram of main outward transporters in cerebral endothelial cells. Some, e.g., PGP, (P-glycoprotein) prevent entry. For others, e.g., MRP (multidrug resistance-associated protein), ligand (drug or toxin) combines with glutathione, glucuronic acid or sulfate in cells before efflux.
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