Review
Transporters of the blood–brain and blood–CSF interfaces in development and in the adult

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Abstract

The protective barriers of the brain provide a complex series of physical and chemical obstacles to movement of macromolecules from the periphery into the central nervous system. Studies on these barriers have been focused on two main research areas: (i) anatomical and physiological descriptions of their properties, including during development where functioning barriers are likely to be important for normal neuronal growth; and (ii), investigations of these barriers during disease and attempts at overcoming their defenses in order to deliver drugs to the central nervous system. Both fields are now advanced by the application of molecular gene expression studies of cerebral endothelia (blood vasculature, site of the blood–brain barrier) and choroid plexus epithelia (site of the blood–cerebrospinal fluid barrier) from developing and adult brains, particularly with respect to solute-linked carriers and other transporters. These new techniques provide a wealth of information on the changing nature of transporters at barrier interfaces during normal development and following disease. This review outlines published findings from transcriptome and qPCR studies of expression of genes coding for transporters in these barriers, with a focus on developing brain. The findings clearly support earlier published physiological data describing specific transport mechanisms across barrier interfaces both in the adult and in particular in the developing brain.

Section snippets

Homeostatic barriers of the brain

The barriers of the brain play critical roles in controlling the movement of various metabolites, but also drugs, between the blood and the brain – determining their concentrations and effects in the central nervous system. Fundamental to all brain barrier mechanisms is the presence of intercellular tight junctions between intimately apposed cells comprising these interfaces. Without such junctions, active and passive transfer mechanisms across the interfaces would be ineffective as diffusion

Molecular identity of transporters of the brain barriers

Each of the individual brain barriers is structurally formed by tight junctions between the cells of the interfaces (Liebner et al., 2011, Saunders et al., 2008, Wolburg et al., 2001). The critical function of these junctions is to join barrier cells together creating a physical barrier to paracellular diffusion, allowing cells to polarize with distinct luminal and abluminal components. The presence of these junctions between cells that form the interface between the periphery and the central

Barrier transporter gene expression in developing brain

Two recent papers describing transcriptome analyses that allow comparison of different stages of development of the blood–brain barrier and blood–CSF barrier have been published: Daneman et al. (2010a) of cerebral endothelial cells in postnatal and adult mouse and Liddelow et al. (2012) of fetal and adult mouse choroid plexus epithelial cells. Both used Affymetrix arrays with confirmation of some genes using qPCR. Of added importance in the work of Daneman et al. (2010a) is the comparison of

Physiological importance of transporters at barrier interfaces

Many SLC transporters regulate the movement of amino acids into the CSF and the developing brain where they are important for normal development (for review see Saunders, 1992). Most are directly involved in protein metabolism underlying cellular growth of the brain. Some are important because they act as carriers, for example, thyroid hormone transporters. The main ones so far described, Slc16a2 (MCT8) and Slco1c1 (Oatp14), have recently been identified in cerebral endothelial and choroid

A note on techniques employed in the reviewed literature

It is widely recognized that the comparison of molecular biologically-derived datasets, such as high throughput gene chip databases, is fraught with dangers and problems (Brazma et al., 2001). It is generally not recommended to compare datasets from different studies for a number of reasons. These include the type of technology used (e.g. Affymetrix genechip arrays, Illumina RNASeq, PCR, SAGE), different chemistries (e.g. Enzo versus IVT labeling kits), batch differences in chip design and

Conclusion

The mammalian brain is anatomically complex, containing diverse cell types and distinct microstructures that are surrounded and protected by a number of physical and physiological brain barriers. The large numbers of SLC transcripts present at both the blood–brain barrier and the blood–CSF barrier are likely to play crucial roles in energy metabolism, nutrient supply, as well as CSF production and neurotransmitter regulation in the brain, particularly during its development. This evidence,

Acknowledgements

N.R.S., K.M.D. and S.A.L. are members of the Neurobid Consortium, funded by the Seventh Framework Program (EU) and the National Health and Medical Research Council, Australia. SAL is funded by the American-Australian Association.

References (48)

  • A. Armulik et al.

    Pericytes regulate the blood–brain barrier

    Nature

    (2010)
  • O. Baud et al.

    Perinatal and early postnatal changes in the expression of monocarboxylate transporters MCT1 and MCT2 in the rat forebrain

    J. Comp. Neurol.

    (2003)
  • L.Z. Bito et al.

    The ontogenesis of haematoencephalic cation transport processes in the rhesus monkey

    J. Physiol.

    (1970)
  • M.W. Bradbury et al.

    Electrolytes and water in the brain and cerebrospinal fluid of the foetal sheep and guinea-pig

    J. Physiol.

    (1972)
  • A. Brazma et al.

    Minimum information about a microarray experiment (MIAME)-toward standards for microarray data

    Nat. Genet.

    (2001)
  • A.S. Bustin et al.

    MIQE guidelines – minimum information for publication of quantitative real-time PCR experiments

    Clin. Chem.

    (2009)
  • B. Chen et al.

    Endocytic sorting and recycling require membrane phosphatidylserine asymmetry maintained by TAT-1/CHAT-1

    PLoS Genet.

    (2010)
  • E.M. Cornford et al.

    Developmental modulations of blood–brain barrier permeability as an indicator of changing nutritional requirements in the brain

    Pediatr. Res.

    (1982)
  • A. Dahlin et al.

    Expression profiling of the solute carrier gene family in the mouse brain

    J. Pharmacol. Exp. Ther.

    (2010)
  • H.H. Damkier et al.

    Epithelial pathways in choroid plexus electrolyte transport

    Physiology

    (2010)
  • R. Daneman et al.

    The mouse blood–brain barrier transcriptome: a new resource for understanding the development and function of brain endothelial cells

    PLoS ONE

    (2010)
  • R. Daneman et al.

    Pericytes are required for blood–brain barrier integrity during embryogenesis

    Nature

    (2010)
  • C.J. Ek et al.

    Functional effectiveness of the blood–brain barrier to small water-soluble molecules in developing and adult opossum (Monodelphis domestica)

    J. Comp. Neurol.

    (2006)
  • C.J. Ek et al.

    Structural characteristics and barrier properties of the choroid plexuses in developing brain of the opossum (Monodelphis domestica)

    J. Comp. Neurol.

    (2003)
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    Publication in part sponsored by the Swiss National Science Foundation through the National Center of Competence in Research (NCCR) TransCure, University of Bern, Switzerland; Director Matthias A. Hediger; Web: http://www.transcure.ch.

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