Abstract
There are five exchange interfaces between the peripheral circulation (blood), the cerebrospinal fluid (CSF) and the brain: (i) meninges, (ii) blood vessels, (iii) choroid plexuses, (iv) circumventricular organs and (v) ependyma (neuroependyma in embryos). All five interfaces have distinctive morphological and physiological properties; the first three are characterised by intercellular tight junctions that provide important structural basis for limiting molecular exchange across their interfaces. Cells that form these interfaces are also sites of extensive exchange mechanisms (transporters) that control entry and exit of a wide variety of molecules into the brain. Secretion of CSF by the choroid plexuses which flows through the ventricular system, and the exchange of substances between the CSF and brain is an important mechanism for the control of the characteristic composition of the brain interstitial fluid. Understanding of the complexity of barrier mechanisms is essential for evaluation of the effects of inflammatory conditions affecting the brain, whether in the adult or during development.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Abbott NJ, Rönnbäck L, Hansson E (2006) Astrocyte-endothelial interactions at the blood–brain barrier. Nat Rev Neurosci 7(1):41–53
Alvarez JI, Katayama T, Prat A (2013) Glial influence on the blood brain barrier. Glia 61(12):1939–1958
Amtorp O, Sørensen SC (1974) The ontogenetic development of concentration differences for protein and ions between plasma and cerebrospinal fluid in rabbits and rats. J Physiol 243:387–400
Armulik A, Genové G, Mäe M et al (2010) Pericytes regulate the blood–brain barrier. Nature 468(7323):557–561
Attwell D, Mishra A, Hall CN et al (2016) What is a pericyte? J Cereb Blood Flow Metab 36(2):451–455
Bailey CG, Ryan RM, Thoeng AD et al (2011) Loss-of-function mutations in the glutamate transporter SLC1A1 cause human dicarboxylic aminoaciduria. J Clin Invest 121(1):446–453
Bass NH, Lundborg P (1973) Postnatal development of bulk flow in the cerebrospinal fluid system of the albino rat: clearance of carboxyl-(14C)inulin after intrathecal infusion. Brain Res 52:323–332
Bauer B, Hartz AMS, Lucking JR et al (2008) Coordinated nuclear receptor regulation of the efflux transporter, Mrp2, and the phase-II metabolizing enzyme, GSTpi, at the blood–brain barrier. J Cereb Blood Flow Metab 28:1222–1234
Bauer HC, Krizbai IA, Bauer H et al (2014) “You Shall Not Pass”-tight junctions of the blood brain barrier. Front Neurosci 8:392. doi:10.3389/fnins.2014.00392
Bito LZ, Myers RE (1970) The ontogenesis of haematoencephalic cation transport in the rhesus monkey. J Physiol (Lond) 208:153–170
Bodoy S, Fotiadis D, Stoeger C et al (2013) The small SLC43 family: facilitator system l amino acid transporters and the orphan EEG1. Mol Aspects Med 34(2–3):638–645
Bradbury MWB, Crowder J, Desai S et al (1972) Electrolytes and water in the brain and cerebrospinal fluid of the foetal sheep and guinea pig. J Physiol (Lond) 227:591–610
Brian OK, Tom P, Wang D (2010) Aquaporins: relevance to cerebrospinal fluid physiology and therapeutic potential in hydrocephalus. CSF Res 7:15.
Brightman MW, Reese TS (1969) Junctions between intimately apposed cell membranes in the vertebrate brain. J Cell Biol 40:48–77
Brøchner CB, Holst CB, Møllgård K (2015) Outer brain barriers in rat and human development. Front Neurosci 9:75. doi:10.3389/fnins.2015.00075
Caley DW, Maxwell DS (1970) Development of the blood vessels and extracellular spaces during postnatal maturation of rat cerebral cortex. J Comp Neurol 138:31–47
Christensen HN, Albritton LM, Kakuda DK et al (1994) Gene-product designations for amino acid transporters. J Exp Biol 196:51–57
Christensen HL, Nguyen AT, Pedersen FD et al (2013) Na(+) dependent acid–base transporters in the choroid plexus; insights from slc4 and slc9 gene deletion studies. Front Physiol 4:304. doi:10.3389/fphys.2013.00304
Christensen IB, Gyldenholm T, Damkier HH et al (2013) Polarization of membrane associated proteins in the choroid plexus epithelium from normal and slc4a10 knockout mice. Front Physiol 4:344. doi:10.3389/fphys.2013.00344
Cooray HC, Blackmore CG, Maskell L et al (2002) Localisation of breast cancer resistance protein in microvessel endothelium of human brain. Neuroreport 13:2059–2063
Damkier HH, Brown PD, Praetorius J (2010) Epithelial pathways in choroid plexus electrolyte transport. Physiology (Bethesda) 25(4):239–249
Damkier HH, Brown PD, Praetorius J (2013) Cerebrospinal fluid secretion by the choroid plexus. Physiol Rev 93(4):1847–1892
Damkier HH, Praetorius J (2012) Genetic ablation of Slc4a10 alters the expression pattern of transporters involved in solute movement in the mouse choroid plexus. Am J Physiol Cell Physiol 302(10):C1452–C1459
Daneman R, Zhou L, Kebede AA et al (2010) Pericytes are required for blood–brain barrier integrity during embryogenesis. Nature 468:562–566
Daneman R, Zhou L, Agalliu D et al (2010) The mouse blood–brain barrier transcriptome: a new resource for understanding the development and function of brain endothelial cells. PLoS One 5:e13741. doi:10.1371/journal.pone.0013741
Daneman R, Prat A (2015) The blood–brain barrier. Cold Spring Harb Perspect Biol 7(1):a020412. doi:10.1101/cshperspect.a020412
Davson H (1956) Physiology of the ocular and cerebrospinal fluids. Churchill, London
Davson H (1967) Physiology of the cerebrospinal fluid. Churchill, London
Davson H, Segal MB (1996) Physiology of the CSF and blood–brain barriers. CRC Press, Boca Raton
Decimo I, Fumagalli G, Berton V et al (2012) Meninges: from protective membrane to stem cell niche. Am J Stem Cells 1(2):92–105
Dore-Duffy P, Cleary K (2011) Morphology and properties of pericytes. Methods Mol Biol 686:49–68
Dore-Duffy P, Esen N, Serkin Z (2015) Chapter 5. The elusive multipotent microvascular pericytes. In: The blood–brain barrier in health and disease vol 1 morphology, biology and immune function. CRC Press, Boca Raton, pp 119–139
Dziegielewska KM, Habgood MD, Møllgård K et al (1991) Species-specific transfer of plasma albumin from blood into different cerebrospinal fluid compartments in the fetal sheep. J Physiol 439:215–237
Ehrlich P (1885) Das Sauerstoffbedürfnis des Organismus. Eine farbenanalytische Studie. Hirschwald, Berlin
Ek CJ, Habgood MD, Dziegielewska KM et al (2006) Functional effectiveness of the blood–brain barrier to small water-soluble molecules in developing and adult opossum (Monodelphis domestica). J Comp Neurol 496:13–26
Ek CJ, Wong A, Liddelow SA et al (2010) Efflux mechanisms at the developing brain barriers: ABC-transporters in the fetal and postnatal rat. Toxicol Lett 197:51–59
ElAli A, Thériault P, Rivest S (2014) The role of pericytes in neurovascular unit remodeling in brain disorders. Int J Mol Sci 15(4):6453–64574
Enerson BE, Drewes LR (2006) The rat blood–brain barrier transcriptome. J Cereb Blood Flow Metab 26(7):959–973
Evans CAN, Reynolds JM, Reynolds ML et al (1974) The development of a blood–brain barrier mechanism in foetal sheep. J Physiol 238(2):371–386
Fossan G, Cavanagh M, Evans CAN et al (1985) CSF-brain permeability in the immature sheep fetus: a CSF-brain barrier. Dev Brain Res 18:113–124
Fotiadis D, Kanai Y, Palacín M (2013) The SLC3 and SLC7 families of amino acid transporters. Mol Aspects Med 34(2–3):39–158
Friesema EC, Jansen J, Jachtenberg JW et al (2008) Effective cellular uptake and efflux of thyroid hormone by human monocarboxylate transporter 10. Mol Endocrinol 22(6):1357–1369
Goldmann EE (1909) Die äussere und innere Sekretion des gesunden und kranken Organismus im Lichte der ‘vitalen Färbung’. Beiträg Klinische Chirurgie 64:192–265
Halestrap AP (2013) The SLC16 gene family – structure, role and regulation in health and disease. Mol Aspects Med 34(2–3):337–349. doi:10.1016/j.mam.2012.05.003
Halestrap AP (2013) Monocarboxylic acid transport. Compr Physiol 3(4):1611–1643. doi:10.1002/cphy.c130008
Hall CN, Reynell C, Gesslein B et al (2014) Capillary pericytes regulate cerebral blood flow in health and disease. Nature 508:55–60
Hartz AMS, Bauer B (2011) ABC transporters in the CNS – an inventory. Curr Pharm Biotechnol 12:656–673
Hill J, Rom S, Ramirez SH et al (2014) Emerging roles of pericytes in the regulation of the neurovascular unit in health and disease. J Neuroimmune Pharmacol 9(5):591–605
Hladky SB, Barrand MA (2014) Mechanisms of fluid movement into, through and out of the brain: evaluation of the evidence. Fluids Barriers CNS 11(1):26. doi:10.1186/2045-8118-11-26
Holash JA, Noden DM, Stewart PA (1993) Re-evaluating the role of astrocytes in blood–brain barrier induction. Dev Dyn 197:14–25
Horstmann E, Meves H (1959) Die Feinstrucktur des moleculären Rindengraues und ihre physiologisches Bedeutung. Z Zellforschung 49:569–604
Hurtado-Alvarado G, Cabañas-Morales AM, Gómez-Gónzalez B (2014) Pericytes: brain-immune interface modulators. Front Integr Neurosci 7:80. doi:10.3389/fnint.2013.00080
Ito Y, Takahashi S, Kagitani-Shimono K et al (2015) Nationwide survey of glucose transporter-1 deficiency syndrome (GLUT-1DS) in Japan. Brain Dev 37(8):780–789
Janzer RC, Raff MC (1987) Astrocytes induce blood–brain barrier properties in endothelial cells. Nature 325:253–257
Jessen NA, Munk AS, Lundgaard I et al (2015) The glymphatic system: a beginner’s guide. Neurochem Res 40(12):2583–2599
Johanson CE, Woodbury DM (1974) Changes in CSF flow and extracellular space in the developing rat. In: Vernadakis A, Weiner N (eds) Drugs and the developing brain. Plenum, New York, pp 281–287
Johansson PA, Dziegielewska KM, Liddelow SA et al (2008) The blood-CSF barrier explained: when development is not immaturity. Bioessays 30(3):237–248
Johnston M, Zakharov A, Papaiconomou C et al (2004) Evidence of connections between cerebrospinal fluid and nasal lymphatic vessels in humans, non-human primates and other mammalian species. Cerebrospinal Fluid Res 1(1):2. doi:10.1186/1743-8454-1-2
Johnston M, Zakharov A, Koh L et al (2005) Subarachnoid injection of Microfil reveals connections between cerebrospinal fluid and nasal lymphatics in the non-human primate. Neuropathol Appl Neurobiol 31(6):632–640
Kanai Y, Clémençon B, Simonin A et al (2013) The SLC1 high-affinity glutamate and neutral amino acid transporter family. Mol Aspects Med 34(2–3):108–120
Koehler-Stec EM, Simpson IA, Vannucci SJ et al (1998) Monocarboxylate transporter expression in mouse brain. Am J Physiol 275(3 Pt 1):E516–E524
Korogod N, Petersen CC, Knott GW (2015) Ultrastructural analysis of adult mouse neocortex comparing aldehyde perfusion with cryo fixation. Elife 4. doi:10.7554/eLife.05793
Kratzer I, Liddelow SA, Saunders NR et al (2013) Developmental changes in the transcriptome of the rat choroid plexus in relation to neuroprotection. Fluids Barriers CNS 10:25. doi:10.1186/2045-8118-10-25
Langlet F, Mullier A, Bouret SG et al (2013) Tanycyte-like cells form a blood-cerebrospinal fluid barrier in the circumventricular organs of the mouse brain. J Comp Neurol 521(15):3389–3405. doi:10.1002/cne.23355
Leino RL, Gerhart DZ, Drewes LR (1999) Monocarboxylate transporter (MCT1) abundance in brains of suckling and adult rats: a quantitative electron microscopic immunogold study. Brain Res Dev Brain Res 113(1–2):47–54
Lewandowsky M (1900) Zur Lehre von der Cerebrospinalflüssigkeit. Z Clin Med 40:480–494
Liddelow SA, Dziegielewska KM, Ek CJ et al (2009) Cellular transfer of macromolecules across the developing choroid plexus of Monodelphis domestica. Eur J Neurosci 29(2):253–266
Liddelow SA, Temple S, Møllgård K et al (2012) Molecular characterisation of transport mechanisms at the developing mouse blood-CSF interface: a transcriptome approach. PLoS One 7:e33554. doi:10.1371/journal.pone.0033554
Liddelow SA, Dziegielewska KM, Ek CJ et al (2013) Mechanisms that determine the internal environment of the developing brain: a transcriptomic, functional and ultrastructural approach. PLoS One 8:e65629. doi:10.1371/journal.pone.0065629.s005
Liddelow SA, Dzięgielewska KM, Møllgård K et al (2014) Cellular specificity of the blood-CSF barrier for albumin transfer across the choroid plexus epithelium. PLoS One 9(9):e106592. doi:10.1371/journal.pone.0106592
Liddelow SA, Dziegielewska KM, Ek CJ (2016) Correction: mechanisms that determine the internal environment of the developing brain: a transcriptomic, functional and ultrastructural approach. PLoS One 11(1):e0147680. doi:10.1371/journal.pone.0147680
Lindahl P, Johansson BR, Levéen P et al (1997) Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277(5323):242–245
Löscher W, Potschka H (2005) Drug resistance in brain diseases and the role of drug efflux transporters. Nat Rev Neurosci 6:591–602
Ma S, Kwon HJ, Huang Z (2012) A functional requirement for astroglia in promoting blood vessel development in the early postnatal brain. PLoS One 7(10):e48001. doi:10.1371/journal.pone.0048001
MacAulay N, Zeuthen T (2010) Water transport between CNS compartments: contributions of aquaporins and cotransporters. Neuroscience 168(4):941–956
Maliepaard M, Scheffer GL, Faneyte IF et al (2001) Subcellular localization and distribution of the breast cancer resistance protein transporter in normal human tissues. Cancer Res 61:3458–3464
Manley GT, Fujimura M, Ma T et al (2000) Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke. Nat Med 6(2):159–163
Marques F, Sousa JC, Coppola G et al (2011) Transcriptome signature of the adult mouse choroid plexus. Fluids Barriers CNS 8(1):10. doi:10.1186/2045-8118-8-10
Møllgård K, Balslev Y, Lauritzen B et al (1987) Cell junctions and membrane specializations in the ventricular zone (germinal matrix) of the developing sheep brain: a CSF-brain barrier. J Neurocytol 16:433–444
Nabeshima S, Reese TS, Landis DM et al (1975) Junctions in the meninges and marginal glia. J Comp Neurol 164:127–169
Neuwelt EA (2004) Mechanisms of disease: the blood–brain barrier. Neurosurgery 54:131–140; discussion 141–142
Nies AT, Jedlitschky G, König J et al (2004) Expression and immunolocalization of the multidrug resistance proteins, MRP1-MRP6 (ABCC1-ABCC6), in human brain. Neuroscience 129:349–360
O’Donnell ME (2015) Chapter 4. The neurovascular unit. In: The blood–brain barrier in health and disease vol 1 morphology, biology and immune function. CRC Press, Boca Raton, pp 86–118
Oldendorf WM (1971) Brain uptake of radiolabeled amino acids, amines, and hexoses after arterial injection. Am J Physiol 221:1629–1639
Oldendorf WH (1971) Uptake of radiolabeled essential amino acids by brain following arterial injection. Proc Soc Exp Biol Med 136:385–386
Oldendorf WH (1977) The blood–brain barrier. Exp Eye Res 25(Suppl):177–190
Oldendorf WH, Davson H (1967) Brain extracellular space and the sink action of cerebrospinal fluid. Measurement of rabbit brain extracellular space using sucrose labeled with carbon 14. Arch Neurol 17(2):196–205
Oldendorf WH, Szabo J (1976) Amino acid assignment to one of three blood–brain barrier amino acid carriers. Am J Physiol 230:94–98
Oshio K, Watanabe H, Song Y et al (2005) Reduced cerebrospinal fluid production and intracranial pressure in mice lacking choroid plexus water channel Aquaporin-1. FASEB J. 9(1):76–78.
Richter JJ, Wainer A (1971) Evidence for separate system for the transport of neutral and basic amino acids across the blood–brain barrier. J Neurochem 18:613–620
Rivas M, Naranjo JR (2007) Thyroid hormones, learning and memory. Genes Brain Behav 6(Suppl 1):40–44
Roberts LM, Black DS, Raman C et al (2008) Subcellular localization of transporters along the rat blood–brain barrier and blood-cerebral-spinal fluid barrier by in vivo biotinylation. Neuroscience 155:423–438
Saunders NR, Liddelow SA, Dziegielewska KM (2012) Barrier mechanisms in the developing brain. Front Neuropharmacol 3:46. doi:10.3389/fphar.2012.00046
Saunders NR, Daneman R, Dziegielewska KM et al (2013) Transporters of the blood–brain and blood-CSF interfaces in development and in the adult. Mol Aspects Med 34:742–752
Saunders NR, Dreifuss J-J, Dziegielewska KM et al (2014) The rights and wrongs of blood–brain barrier permeability studies: a walk through 100 years of history. Front Neurosci 8:1–26. doi:10.3389/fnins.2014.00404/abstract
Saunders NR, Dziegielewska KM, Møllgård K et al (2015) Influx mechanisms in the embryonic and adult rat choroid plexus: a transcriptome study. Front Neurosci 9:123. doi:10.3389/fnins.2015.00123
Saunders NR, Habgood MD, Møllgård K et al (2016) The biological significance of brain barrier mechanisms: help or hindrance in drug delivery to the central nervous system? F1000Res 5. pii: F1000 Faculty Rev-313. doi:10.12688/f1000research.7378.1
Schumacher U, Møllgård K (1997) The multidrug-resistance P-glycoprotein (Pgp, MDR1) is an early marker of blood–brain barrier development in the microvessels of the developing human brain. Histochem Cell Biol 108:179–182
Simonová Z, Svoboda J, Orkand P et al (1996) Changes of extracellular space volume and tortuosity in the spinal cord of Lewis rats with experimental autoimmune encephalomyelitis. Physiol Res 45:11–22
Skeaff SA (2011) Iodine deficiency in pregnancy: the effect on neurodevelopment in the child. Nutrients 3(2):265–273
Smith DE, Streicher E, Milkovic K et al (1964) Observations on the transport of proteins by the isolated choroid plexus. Acta Neuropathol 3:372–386
Spector R (2009) Nutrient transport systems in brain: 40 years of progress. J Neurochem 111(2):315–320
Spector R, Robert Snodgrass S, Johanson CE (2015) A balanced view of the cerebrospinal fluid composition and functions: Focus on adult humans. Exp Neurol 273:57–68
Sperandeo MP, Borsani G, Incerti B et al (1998) The gene encoding a cationic amino acid transporter (SLC7A4) maps to the region deleted in the velocardiofacial syndrome. Genomics 49(2):230–236
Stern L, Gautier R (1918) Le passage dans le liquide céphalo-rachidien de substances introduites dans la circulation et leur action sur le système nerveux central chez les différentes espèces animales. R C R d Ia Soc de Phys et d’hist natur de Genève 35:91–94
Strazielle N, Ghersi-Egea J-F (2015) Efflux transporters in blood–brain interfaces of the developing brain. Front Neurosci 9:1–11. doi:10.3389/fnins.2015.00021
Syková E, Nicholson C (2008) Diffusion in brain extracellular space. Physiol Rev 88:1277–1340
Vannucci SJ, Seaman LB, Brucklacher RM et al (1994) Glucose transport in developing rat brain: glucose transporter proteins, rate constants and cerebral glucose utilization. Mol Cell Biochem 140(2):177–184
Vannucci SJ, Simpson IA (2003) Developmental switch in brain nutrient transporter expression in he rat. Am J Physiol Endocrinol Metab 285(5):E1127–E1134
Vannucci RC, Vannucci SJ (2000) Glucose metabolism in the developing brain. Semin Perinatol 24(2):107–115
Virgintino D, Errede M, Girolamo F et al (2008) Fetal blood–brain barrier P-glycoprotein contributes to brain protection during human development. J Neuropathol Exp Neurol 67:50–61
Vorísek I, Syková E (1997) Ischemia-induced changes in the extracellular space diffusion parameters, K+, and pH in the developing rat cortex and corpus callosum. J Cereb Blood Flow Metab 17(2):191–203
Whish S, Dziegielewska K, Møllgård K et al (2015) The inner CSF–brain barrier: developmentally controlled access to the brain via intercellular junctions. Front Neurosci 9:115. doi:10.3389/fnins.2015.00016
Wright EM (2013) Glucose transport families SLC5 and SLC50. Mol Aspects Med 34:183–196
Wyckoff RW, Young JZ (1956) The motorneuron surface. Proc R Soc Lond B Biol Sci 144(917):440–450
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2017 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Saunders, N.R., Dziegielewska, K.M., Møllgård, K., Habgood, M.D. (2017). General Introduction to Barrier Mechanisms in the Central Nervous System. In: Lyck, R., Enzmann, G. (eds) The Blood Brain Barrier and Inflammation. Progress in Inflammation Research. Springer, Cham. https://doi.org/10.1007/978-3-319-45514-3_1
Download citation
DOI: https://doi.org/10.1007/978-3-319-45514-3_1
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-45512-9
Online ISBN: 978-3-319-45514-3
eBook Packages: MedicineMedicine (R0)