Cerebrospinal fluid secretion by the choroid plexus

Damkier, Helle H.; Brown, Peter D.; Praetorius, Jeppe

doi:10.1152/physrev.00004.2013

Cited by 609Cerebrospinal fluid and hydrocephalusIon Transport and Channel RegulationBarrier Structure and Function Studies

Cerebrospinal fluid secretion by the choroid plexus

Damkier, Helle H., Brown, Peter D., Praetorius, Jeppe·2013·Physiological Reviews

DOI 10.1152/physrev.00004.2013

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Abstract

The choroid plexus epithelium is a cuboidal cell monolayer, which produces the majority of the cerebrospinal fluid. The concerted action of a variety of integral membrane proteins mediates the transepithelial movement of solutes and water across the epithelium. Secretion by the choroid plexus is characterized by an extremely high rate and by the unusual cellular polarization of well-known epithelial transport proteins. This review focuses on the specific ion and water transport by the choroid plexus cells, and then attempts to integrate the action of specific transport proteins to formulate a model of cerebrospinal fluid secretion. Significant emphasis is placed on the concept of isotonic fluid transport across epithelia, as there is still surprisingly little consensus on the basic biophysics of this phenomenon. The role of the choroid plexus in the regulation of fluid and electrolyte balance in the central nervous system is discussed, and choroid plexus dysfunctions are described in a very diverse set of clinical conditions such as aging, Alzheimer's disease, brain edema, neoplasms, and hydrocephalus. Although the choroid plexus may only have an indirect influence on the pathogenesis of these conditions, the ability to modify epithelial function may be an important component of future therapies.

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The ChP epithelial sheet, together with vasculature and diverse cell types, regulates CSF secretion and composition by de novo protein synthesis and selective transcytosis of blood-borne factors.
“The foundation of the ChP is an epithelial sheet that, together with a network of vasculature and diverse cell types, regulates CSF secretion and governs its composition by de novo protein synthesis and selective transcytosis of blood-borne factors (Damkier et al., 2013; Ghersi-Egea et al., 2018; Lun et al., 2015a; Saunders et al., 2018b).”
From A cellular and spatial map of the choroid plexus across brain ventricles and ages (2021) · cites this paper as Damkier et al., 2013
The choroid plexus in each brain ventricle produces cerebrospinal fluid and forms the blood-CSF barrier.
“The choroid plexus (ChP) in each brain ventricle produces cerebrospinal fluid (CSF) and forms the blood-CSF barrier.”
From A cellular and spatial map of the choroid plexus across brain ventricles and ages (2021) · cites this paper as Damkier et al., 2013
Age-dependent expression of transporters and channels involved in ion and water movement across the epithelium was found.
“We found age-dependent expression of transporters and channels involved in ion and water movement across the epithelium, aligning with a key function of epithelial cells to produce CSF (Damkier et al., 2013; Fame and Lehtinen, 2020).”
From A cellular and spatial map of the choroid plexus across brain ventricles and ages (2021) · cites this paper as Damkier et al., 2013

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Saito, Y., & Wright, E. M. (1984) · The Journal of Physiology · doi:10.1113/jphysiol.1984.sp015204 · Cited by 89 · see citing works
Aquaporin-1 in the choroid plexuses of developing mammalian brain
Johansson, P. A., Dzięgielewska, K. M., Ek, C. J., Habgood, M. D., Møllgård, K., Potter, A., Schuliga, M. J., & Saunders, N. R. (2005) · Cell and Tissue Research · doi:10.1007/s00441-005-1120-x · Cited by 89 · see citing works
A look at tricellulin and its role in tight junction formation and maintenance
Mariano, C., Sasaki, H., Brites, D. M. T. O., & Brito, M. A. (2011) · European Journal of Cell Biology · doi:10.1016/j.ejcb.2011.06.005 · Cited by 89 · see citing works
Mechanisms of Aldosterone's Action on Epithelial Na + Transport
Eaton, D. C., Malik, B., Nk, S., Al-Khalili, O. K., & Yue, G. (2001) · The Journal of Membrane Biology · doi:10.1007/s00232-001-0098-x · Cited by 88 · see citing works
Brain sodium channels and ouabainlike compounds mediate central aldosterone-induced hypertension
Wang, H., Huang, B. S., & Leenen, F. H. H. (2003) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00299.2003 · Cited by 87 · see citing works
Purification of mouse brain (Na+ + K+)-ATPase catalytic unit, characterization of antiserum, and immunocytochemical localization in cerebellum, choroid plexus, and kidney.
Siegel, G. J., Holm, C., Schreiber, J. H., Desmond, T. J., & Ernst, S. A. (1984) · Journal of Histochemistry & Cytochemistry · doi:10.1177/32.12.6094658 · Cited by 87 · see citing works
Immunocytochemical localization of Na+,K+-ATPase catalytic polypeptide in mouse choroid plexus.
Ernst, S. A., Palacios, J., & Siegel, G. J. (1986) · Journal of Histochemistry & Cytochemistry · doi:10.1177/34.2.3003182 · Cited by 87 · see citing works
Studies on the Cerebro-Spinal Fluid : I. Introduction.
Cushing, H. (1914) · PubMed · Cited by 86 · see citing works
Choroid plexus and ageing in rats: a morphometric and ultrastructural study
Sérot, J., Foliguet, B., Béné, M., & Faure, G. (2001) · European Journal of Neuroscience · doi:10.1046/j.0953-816x.2001.01693.x · Cited by 86 · see citing works
Neuronal polarization and the cytoskeleton
Neukirchen, D., & Bradke, F. (2011) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2011.08.007 · Cited by 85 · see citing works
Water permeability and pathways in the proximal tubule
Berry, C. A. (1983) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.1983.245.3.f279 · Cited by 83 · see citing works
AVP V1 receptor-mediated decrease in Cl− efflux and increase in dark cell number in choroid plexus epithelium
Johanson, C. E., Preston, J. E., Chodobski, A., Stopa, E. G., Szmydynger‐Chodobska, J., & McMillan, P. N. (1999) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.1999.276.1.c82 · Cited by 81 · see citing works
Involvement of Vasopressin in Brain Edema Formation: Further Evidence Obtained from the Brattleboro Diabetes Insipidus Rat with Experimental Subarachnoid Hemorrhage
Doczi, T. P., ́, F. A. L. ́., Szerdahelyi, P., & Joó, F. (1984) · Neurosurgery · doi:10.1227/00006123-198404000-00008 · Cited by 80 · see citing works
Ascorbic Acid and Rates of Cognitive Decline in Alzheimer's Disease
Bowman, G. L., Dodge, H. H., Frei, B. B., Calabrese, C., Oken, B., Kaye, J. A., & Quinn, J. F. (2009) · Journal of Alzheimer s Disease · doi:10.3233/jad-2009-0923 · Cited by 78 · see citing works
Clearance of Amyloid-β Peptide Across the Choroid Plexus in Alzheimers Disease
Alvira, X., & Carro, E. (2010) · Current Aging Science · doi:10.2174/1874609811003030219 · Cited by 78 · see citing works
Carbachol inhibits Na+-K+-ATPase activity in choroid plexus via stimulation of the NO/cGMP pathway
Ellis, D. Z., Nathanson, J. A., & Sweadner, K. J. (2000) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.2000.279.6.c1685 · Cited by 78 · see citing works
Vitamin B12 levels in serum and cerebrospinal fluid of people with Alzheimer's disease
Ikeda, T., Furukawa, Y., Mashimoto, S., Takahashi, K., & Yamada, M. (1990) · Acta Psychiatrica Scandinavica · doi:10.1111/j.1600-0447.1990.tb01395.x · Cited by 77 · see citing works
Molecular Characterisation of Transport Mechanisms at the Developing Mouse Blood–CSF Interface: A Transcriptome Approach
Liddelow, S. A., Temple, S., Møllgård, K., Gehwolf, R., Wagner, A., Bauer, H., Bauer, H., Phoenix, T. N., Dzięgielewska, K. M., & Saunders, N. R. (2012) · PLoS ONE · doi:10.1371/journal.pone.0033554 · Cited by 76 · see citing works

Flagged first, then by citations

3 of the 364 references couldn’t be matched to a known paper.

Sorted by citations

The glymphatic system: a beginner's guide
Jessen, N. A., Munk, A. S. F., Lundgaard, I., & Nedergaard, M. (2015) · Neurochemical Research · doi:10.1007/s11064-015-1581-6 · Cited by 2,075 · see citing works
“CSF production at the choroid plexus is mediated by exchange and transport of ions (especially Cl, Na and HCO3 ) across the epithelial cells, which generates an osmotic gradient that drives the movement of water from the blood to the ventricle lumen [4, 5, 9].”
Influential
Integrating liquid biopsies into the management of cancer
Siravegna, G., Marsoni, S., Siena, S., & Bardelli, A. (2017) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2017.14 · Cited by 1,941 · see citing works
The Glymphatic System in Central Nervous System Health and Disease: Past, Present, and Future
Plog, B. A., & Nedergaard, M. (2017) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-051217-111018 · Cited by 780 · see citing works
“For a comprehensive treatment of choroidal CSF secretion see (8); for purposes of this discussion, the major molecular species involved in this process will be briefly reviewed.”
BackgroundMethodInfluential
Hydrocephalus in children
Kahle, K. T., Kulkarni, A. V., Limbrick, D. D., & Warf, B. C. (2015) · The Lancet · doi:10.1016/s0140-6736(15)60694-8 · Cited by 725 · see citing works
Development and functions of the choroid plexus–cerebrospinal fluid system
Lun, M. P., Monuki, E. S., & Lehtinen, M. K. (2015) · Nature reviews. Neuroscience · doi:10.1038/nrn3921 · Cited by 682 · see citing works
Understanding the functions and relationships of the glymphatic system and meningeal lymphatics
Louveau, A., Plog, B. A., Antila, S., Alitalo, K., Nedergaard, M., & Kipnis, J. (2017) · Journal of Clinical Investigation · doi:10.1172/jci90603 · Cited by 640 · see citing works
“Endothelial LRP1 transports amyloid-β(1-42) across the blood-brain barrier.”
Mechanisms of fluid movement into, through and out of the brain: evaluation of the evidence
Hladky, S. B., & Barrand, M. A. (2014) · Fluids and Barriers of the CNS · doi:10.1186/2045-8118-11-26 · Cited by 633 · see citing works
“[15] the choroid plexus has all the hallmarks of a high capacity secretory epithelium whose product is isosmotic with plasma.”
Background
Fluid transport in the brain
Rasmussen, M. K., Mestre, H., & Nedergaard, M. (2021) · Physiological Reviews · doi:10.1152/physrev.00031.2020 · Cited by 622 · see citing works
Understanding idiopathic intracranial hypertension: mechanisms, management, and future directions
Markey, K. A., Mollan, S. P., Jensen, R., & Sinclair, A. J. (2015) · The Lancet Neurology · doi:10.1016/s1474-4422(15)00298-7 · Cited by 537 · see citing works
Inflammation-dependent cerebrospinal fluid hypersecretion by the choroid plexus epithelium in posthemorrhagic hydrocephalus
Karimy, J. K., Zhang, J., Kurland, D. B., Theriault, B. C., Durán, D., Stokum, J. A., Furey, C. G., Zhou, X., Mansuri, M. S., Montejo, J. D., et al. (2017) · Nature Medicine · doi:10.1038/nm.4361 · Cited by 411 · see citing works
Infantile hydrocephalus: A review of epidemiology, classification and causes
Tully, H. M., & Dobyns, W. B. (2014) · European Journal of Medical Genetics · doi:10.1016/j.ejmg.2014.06.002 · Cited by 410 · see citing works
“In the most familiar model of cerebrospinal fluid (CSF) flow, CSF is produced primarily by the choroid plexi, unique secretory structures located within the lateral, third, and fourth ventricles [Damkier et al., 2013].”
Neuroimmune Axes of the Blood–Brain Barriers and Blood–Brain Interfaces: Bases for Physiological Regulation, Disease States, and Pharmacological Interventions
Erickson, M. A., & Banks, W. A. (2018) · Pharmacological Reviews · doi:10.1124/pr.117.014647 · Cited by 393 · see citing works
“These apical projections provide a large surface area for secretory activity, and also have functions in regulating and sensing pH, osmolarity, and ion balance in CSF (Damkier et al., 2013).”
BackgroundInfluential
A cellular and spatial map of the choroid plexus across brain ventricles and ages
Dani, N., Herbst, R. H., McCabe, C., Green, G. S., Kaiser, K., Head, J. P., Cui, J., Shipley, F. B., Jang, A., Dionne, D., et al. (2021) · Cell · doi:10.1016/j.cell.2021.04.003 · Cited by 388 · see citing works
Lymphatic Clearance of the Brain: Perivascular, Paravascular and Significance for Neurodegenerative Diseases
Bakker, E. N. T. P., Bacskai, B. J., Arbel-Ornath, M., Aldea, R., Bedussi, B., Morris, A. W. J., Weller, R. O., & Carare, R. O. (2016) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-015-0273-8 · Cited by 353 · see citing works
“However, as reviewed by (Damkier et al. 2013), a tight barrier is formed by the epithelial cells at the surface of the choroid plexus.”
Background
Regulation of cerebrospinal fluid (CSF) flow in neurodegenerative, neurovascular and neuroinflammatory disease
Simon, M. J., & Iliff, J. J. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2015.10.014 · Cited by 339 · see citing works
“In addition to playing key roles in the secretion of CSF at the CP, these transporters may also participate in the movement of water between glial cells and the surrounding interstitial and perivascular compartment [15].”
BackgroundInfluential
Choroid plexus and the blood–cerebrospinal fluid barrier in disease
Solár, P., Zamani, A., Kubíčková, L., Dubový, P., & Joukal, M. (2020) · Fluids and Barriers of the CNS · doi:10.1186/s12987-020-00196-2 · Cited by 365 · see citing works
Cerebrospinal fluid dynamics and intracranial pressure elevation in neurological diseases
Bothwell, S. W., Janigro, D., & Patabendige, A. (2019) · Fluids and Barriers of the CNS · doi:10.1186/s12987-019-0129-6 · Cited by 331 · see citing works
Fluid and ion transfer across the blood–brain and blood–cerebrospinal fluid barriers; a comparative account of mechanisms and roles
Hladky, S. B., & Barrand, M. A. (2016) · Fluids and Barriers of the CNS · doi:10.1186/s12987-016-0040-3 · Cited by 291 · see citing works
“[4] the epithelial layer has all the hallmarks of a “leaky” secretory epithelium designed to produce a large volume of nearly isosmotic fluid.”
BackgroundResultInfluential
Cytokines in CAR T Cell–Associated Neurotoxicity
Gust, J., Ponce, R. A., Liles, W. C., Garden, G. A., & Turtle, C. J. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.577027 · Cited by 268 · see citing works
“Molecules are trafficked across the epithelial barriers of the choroid plexus into the CSF (61), which is distinct from the active transport of cytokines from the blood into the brain parenchyma via the neurovascular unit (62).”
Background
The rights and wrongs of blood-brain barrier permeability studies: a walk through 100 years of history
Saunders, N. R., Dreifuss, J.-J., Dzięgielewska, K. M., Johansson, P. A., Habgood, M. D., MÃ¸llgÃ¥rd, K., & Bauer, H. (2014) · Frontiers in Neuroscience · doi:10.3389/fnins.2014.00404 · Cited by 261 · see citing works
Inflammation in acquired hydrocephalus: pathogenic mechanisms and therapeutic targets
Karimy, J. K., Reeves, B. C., Damisah, E. C., Duy, P. Q., Antwi, P., David, W. B., Wang, K. X.-L., Schiff, S. J., Limbrick, D. D., Alper, S. L., et al. (2020) · Nature Reviews Neurology · doi:10.1038/s41582-020-0321-y · Cited by 232 · see citing works
Molecular mechanisms of brain water transport
MacAulay, N. (2021) · Nature reviews. Neuroscience · doi:10.1038/s41583-021-00454-8 · Cited by 229 · see citing works
A balanced view of choroid plexus structure and function: Focus on adult humans
Spector, R., Keep, R. F., Snodgrass, S. R., Smith, Q. R., & Johanson, C. E. (2015) · Experimental Neurology · doi:10.1016/j.expneurol.2015.02.032 · Cited by 218 · see citing works
“There is longstanding recognition that CP is the source of energy-requiring CSF formation and pressure generation in the ventricles (Netsky and Shuangshoti, 1975), and modern physiologic and molecular techniques continually substantiate this concept (Damkier et al., 2013; Millar et al., 2007).”
Influential
Cotransporter-mediated water transport underlying cerebrospinal fluid formation
Steffensen, A. B., Oernbo, E. K., Stoica, A., Gerkau, N. J., Barbuskaite, D., Tritsaris, K., Rose, C. R., & MacAulay, N. (2018) · Nature Communications · doi:10.1038/s41467-018-04677-9 · Cited by 221 · see citing works
“However, several observations suggest that such a simple osmotic model may not be adequate: (1) The CSF production declined by a mere 20% in the AQP1 knock-out mice, partly ascribed to the 80% reduction of central venous blood pressure in these mice15.”
Intracellular pH regulation by acid-base transporters in mammalian neurons
Ruffin, V. A., Salameh, A., Boron, W. F., & Parker, M. D. (2014) · Frontiers in Physiology · doi:10.3389/fphys.2014.00043 · Cited by 212 · see citing works
“Finally, we must not discount the contribution of acid-base transporters in the astrocytes (Chesler, 2003) and choroid plexus epithelia (Damkier et al., 2010a, 2013), cells that control the composition of the brain extracellular fluid and thus indirectly influence the pH of neurons.”
Background
Elimination of substances from the brain parenchyma: efflux via perivascular pathways and via the blood–brain barrier
Hladky, S. B., & Barrand, M. A. (2018) · Fluids and Barriers of the CNS · doi:10.1186/s12987-018-0113-6 · Cited by 206 · see citing works
The Glymphatic Pathway: Waste Removal from the CNS via Cerebrospinal Fluid Transport
Benveniste, H., Lee, H., & Volkow, N. D. (2017) · The Neuroscientist · doi:10.1177/1073858417691030 · Cited by 203 · see citing works
Age-Associated Changes in the Immune System and Blood–Brain Barrier Functions
Erickson, M. A., & Banks, W. A. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20071632 · Cited by 192 · see citing works
“The CPE is the major site of cerebrospinal fluid (CSF) production, and CPE transporters are important for regulating CSF composition (reviewed in [67]).”
Background
Emerging roles for CNS fibroblasts in health, injury and disease
Dorrier, C., Jones, H. E., Pintarić, L., Siegenthaler, J. A., & Daneman, R. (2021) · Nature reviews. Neuroscience · doi:10.1038/s41583-021-00525-w · Cited by 194 · see citing works
Glymphatic System Function in Relation to Anesthesia and Sleep States
Benveniste, H., Heerdt, P. M., Fontes, M. L., Rothman, D. L., & Volkow, N. D. (2019) · Anesthesia & Analgesia · doi:10.1213/ane.0000000000004069 · Cited by 178 · see citing works
Nanomaterial based drug delivery systems for the treatment of neurodegenerative diseases
Masoudi Asil, S., Ahlawat, J., Guillama Barroso, G., & Narayan, M. (2020) · Biomaterials Science · doi:10.1039/d0bm00809e · Cited by 181 · see citing works
Intrathecal drug delivery in the era of nanomedicine
Fowler, M. J., Cotter, J. D., Knight, B. E., Sevick-Muraca, E. M., Sandberg, D. I., & Sirianni, R. W. (2020) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.02.006 · Cited by 187 · see citing works
“Small perturbations in osmolality and pH can stimulate significant changes to CSF secretion that are expected to impact flow.[21]”
Background
Spatially Heterogeneous Choroid Plexus Transcriptomes Encode Positional Identity and Contribute to Regional CSF Production
Lun, M. P., Johnson, M. B., Broadbelt, K. G., Watanabe, M., Kang, Y., Chau, K. F., Springel, M. W., Malesz, A., Sousa, A. M. M., Pletikos, M., et al. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.3081-14.2015 · Cited by 178 · see citing works
“However, in vivo CSF is home to signals derived from sources other than the ChP, including the ventricular lining, vasculature, interstitial fluid, and axons innervating the ventricular walls (Johanson et al., 2008; Damkier et al., 2013).”
BackgroundInfluential
The Choroid Plexus in Healthy and Diseased Brain
Kaur, C., Rathnasamy, G., & Ling, E.-A. (2016) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/nlv030 · Cited by 176 · see citing works
“This provides an electrochemical gradient for the active transport of various molecules that are involved in the secretion of CSF (32).”
Background
Cerebrospinal fluid production by the choroid plexus: a century of barrier research revisited
MacAulay, N., Keep, R. F., & Zeuthen, T. (2022) · Fluids and Barriers of the CNS · doi:10.1186/s12987-022-00323-1 · Cited by 165 · see citing works
“HCO3 transporters are key to CSF secretion [30, 69, 78].”
BackgroundMethodInfluential
A glucagon-like peptide-1 receptor agonist reduces intracranial pressure in a rat model of hydrocephalus
Botfield, H. F., Uldall, M., Westgate, C. S. J., Mitchell, J., Hagen, S. M., Gonzalez, A. M., Hodson, D. J., Jensen, R., & Sinclair, A. J. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aan0972 · Cited by 164 · see citing works
Acid–base physiology, neurobiology and behaviour in relation to CO2-induced ocean acidification
Tresguerres, M., & Hamilton, T. J. (2017) · Journal of Experimental Biology · doi:10.1242/jeb.144113 · Cited by 153 · see citing works
“Can this process result in changes in [Cl−] and [HCO3 −] in the CSF consistent with the GABAAR model? This question can only be answered by performing experiments to elucidate fish CSF and BIF composition and regulatory mechanisms, which should consider the following points: (1) the high PCO2 and low pH in the CSF imp…”
Background
The choroid plexus links innate immunity to CSF dysregulation in hydrocephalus
Robert, S. M., Reeves, B. C., Kiziltug, E., Duy, P. Q., Karimy, J. K., Mansuri, M. S., Marlier, A., Allington, G., Greenberg, A. B. W., DeSpenza, T., et al. (2023) · Cell · doi:10.1016/j.cell.2023.01.017 · Cited by 160 · see citing works
“The ChP is the body’s secretory epithelium par excellence, producing a half-liter of CSF per day via the concerted action of its multiple ion and water transport molecules.(7) The ChP is also the blood-CSF barrier, gating circulating immune cell entry into the CSF in the setting of infection or tissue damage.”
Background
Anatomical basis and physiological role of cerebrospinal fluid transport through the murine cribriform plate
Norwood, J. N., Zhang, Q., Card, D., Craine, A., Ryan, T. M., & Drew, P. J. (2019) · eLife · doi:10.7554/elife.44278 · Cited by 144 · see citing works
Lipid Transport and Metabolism at the Blood-Brain Interface: Implications in Health and Disease
Pifferi, F., Laurent, B., & Plourde, M. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.645646 · Cited by 147 · see citing works
Choroid plexus volume is associated with levels of CSF proteins: relevance for Alzheimer's and Parkinson's disease
Tadayon, E., Pascual‐Leone, Á., Press, D. Z., & Santarnecchi, E. (2020) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2020.01.005 · Cited by 144 · see citing works
The biological significance of brain barrier mechanisms: help or hindrance in drug delivery to the central nervous system?
Saunders, N. R., Habgood, M. D., Møllgård, K., & Dziegielewska, K. M. (2016) · F1000Research · doi:10.12688/f1000research.7378.1 · Cited by 143 · see citing works
Nonsurgical therapy for hydrocephalus: a comprehensive and critical review
Bigio, M. R. D., & Curzio, D. L. D. (2015) · Fluids and Barriers of the CNS · doi:10.1186/s12987-016-0025-2 · Cited by 144 · see citing works
“Cerebrospinal fluid production and brain fluids Readers are referred to other reviews for comprehensive considerations of choroid plexus function including CSF production [15–17], flow of brain fluids through intercellular and paravascular compartments [18–21], and CSF absorption [22, 23].”
Background
The choroid plexus: a missing link in our understanding of brain development and function
Saunders, N. R., Dzięgielewska, K. M., Fame, R. M., Lehtinen, M. K., & Liddelow, S. A. (2022) · Physiological Reviews · doi:10.1152/physrev.00060.2021 · Cited by 141 · see citing works
A Brief Overview of the Cerebrospinal Fluid System and Its Implications for Brain and Spinal Cord Diseases
Wichmann, T. O., Damkier, H. H., & Pedersen, M. (2022) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2021.737217 · Cited by 141 · see citing works
“The fluid is a mixture of water, proteins at low concentrations, ions, neurotransmitters, and glucose that is renewed three to four times per day (Damkier et al., 2013; Hladky and Barrand, 2014; Spector et al., 2015).”
Background
Choroid Plexus Enlargement Exacerbates White Matter Hyperintensity Growth through Glymphatic Impairment
Li, Y., Zhou, Y., Zhong, W., Xiao, Z., Chen, Y., Zhang, K., He, Y., Luo, Z., Wang, R., Sun, J., et al. (2023) · Annals of Neurology · doi:10.1002/ana.26648 · Cited by 135 · see citing works
“Several pieces of evidence have suggested that higher CP volume is correlated with lower rate of CSF secretion,(6) which results in reduced CSF turnover.(3) The pathological changes of enlarged CP, including basement membrane thickening, increased infiltration of fibroblasts and immune cells, and deposition of intrace…”
Background
Role of choroid plexus in cerebrospinal fluid hydrodynamics
Orešković, D., Radoš, M., & Klarica, M. (2017) · Neuroscience · doi:10.1016/j.neuroscience.2017.04.025 · Cited by 133 · see citing works
Choroid plexus NKCC1 mediates cerebrospinal fluid clearance during mouse early postnatal development
Xu, H., Fame, R. M., Sadegh, C., Sutin, J. D. B., Naranjo, C., Syau, D., Cui, J., Shipley, F. B., Vernon, A. N., Gao, F., et al. (2021) · Nature Communications · doi:10.1038/s41467-020-20666-3 · Cited by 129 · see citing works
Transport across the choroid plexus epithelium
Prætorius, J., & Damkier, H. H. (2017) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00041.2017 · Cited by 126 · see citing works
“Since the above mentioned early discoveries by de Rougemont and colleagues (47), evidence to support the CPE as a CSF-producing tissue has been published in abundance and reviewed several times (33, 37, 66, 158).”
Background
Single-cell RNA sequencing reveals microglia-like cells in cerebrospinal fluid during virologically suppressed HIV
Farhadian, S., Mehta, S. S., Zografou, C., Robertson, K., Price, R. W., Pappalardo, J. L., Chiarella, J., Hafler, D. A., & Spudich, S. (2018) · JCI Insight · doi:10.1172/jci.insight.121718 · Cited by 122 · see citing works
Tracking Calcium Dynamics and Immune Surveillance at the Choroid Plexus Blood-Cerebrospinal Fluid Interface
Shipley, F. B., Dani, N., Xu, H., Deister, C., Cui, J., Head, J. P., Sadegh, C., Fame, R. M., Shannon, M. L., Flores, V. I., et al. (2020) · Neuron · doi:10.1016/j.neuron.2020.08.024 · Cited by 118 · see citing works
Modulation of brain cation-Cl− cotransport via the SPAK kinase inhibitor ZT-1a
Zhang, J., Bhuiyan, M. I. H., Zhang, T., Karimy, J. K., Wu, Z., Fiesler, V. M., Zhang, J., Huang, H., Hasan, M. N., Skrzypiec, A. E., et al. (2020) · Nature Communications · doi:10.1038/s41467-019-13851-6 · Cited by 111 · see citing works
The choroid plexus and its role in the pathogenesis of neurological infections
Thompson, D., Brissette, C. A., & Watt, J. A. (2022) · Fluids and Barriers of the CNS · doi:10.1186/s12987-022-00372-6 · Cited by 110 · see citing works
“series of passive diffusion and active ion exchange across the polarized epithelial membrane creates an osmotic gradient that drives the secretion of water into the CSF that is facilitated by aquaporins [15].”
Background
Macrophages on the margin: choroid plexus immune responses
Cui, J., Xu, H., & Lehtinen, M. K. (2021) · Trends in Neurosciences · doi:10.1016/j.tins.2021.07.002 · Cited by 110 · see citing works
The choroid plexus in health and in disease: dialogues into and out of the brain
Marques, F., Sousa, J. C., Brito, M. A., Pahnke, J., Santos, C. R. A., Correia‐Neves, M., & Palha, J. A. (2016) · Neurobiology of Disease · doi:10.1016/j.nbd.2016.08.011 · Cited by 106 · see citing works
Clearance from the mouse brain by convection of interstitial fluid towards the ventricular system
Bedussi, B., van Lier, M. G. J. T. B., Bartstra, J. W., de Vos, J., Siebes, M., VanBavel, E., & Bakker, E. N. T. P. (2015) · Fluids and Barriers of the CNS · doi:10.1186/s12987-015-0019-5 · Cited by 102 · see citing works
“Thus, CSF and ISF may exchange over the ependymal epithelium that covers the ventricular system [7, 8], and CSF may also reenter the parenchyma along paravascular pathways [4, 6, 9].”
Background
Potential Pathways for CNS Drug Delivery Across the Blood-Cerebrospinal Fluid Barrier
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Harnessing cerebrospinal fluid circulation for drug delivery to brain tissues
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“product of arterial blood ultrafiltration [119], and about 20% of its proteins are derived from the brain [120,121].”
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Topiramate is more effective than acetazolamide at lowering intracranial pressure
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“CSF secretion involves numerous enzymes, ion channels and transporters that produce a net movement of ions across the choroid plexus epithelium, thus creating an osmotic gradient that drives water from the blood stream into the ventricles (17).”
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Developing pressures: fluid forces driving morphogenesis
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Selenium and Other Trace Elements in the Etiology of Parkinson’s Disease: A Systematic Review and Meta-Analysis of Case-Control Studies
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Genetic and pharmacological inactivation of apical Na + -K + -2Cl − cotransporter 1 in choroid plexus epithelial cells reveals the physiological function of the cotransporter
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“CPECs are unique among Cl secretory epithelial cells because the Na -K -2Cl cotransporter NKCC1 (SLC12A1) and the Na -K transporting adenosine triphosphatase (Na -K -ATPase) are located on their apical membrane (CSF-facing), deviating from typical basolateral membrane (blood-facing) location (3, 15).”
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Choroid plexus function in neurological homeostasis and disorders: The awakening of the circadian clocks and orexins
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“(ISF) that functions to restrict access to the brain parenchyma.(19) On the other hand, the BCSFB is comprised of the choroidal epithelium and the adjacent”
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Measurements of cerebrospinal fluid production: a review of the limitations and advantages of current methodologies
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“It is well known that the primary role of the BCSFB is to prevent the free passage of molecules between the blood and the CSF, and the main function of the choroid plexus is to the production and regulation of the CSF [2,14,27,59].”
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Deconstructing the functional neuroanatomy of the choroid plexus: an ontogenetic perspective for studying neurodevelopmental and neuropsychiatric disorders
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“Targeting the CP barrier may be a surrogate brain delivery strategy to circumvent the BBB.”
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“It is generally assumed that CSF secretion takes place by conventional osmotic water transport, where water follows the osmotic gradient that results from electrolyte transport across the choroid plexus epithelium [14].”
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Kedarasetti, R. T., Turner, K. L., Echagarruga, C., Gluckman, B. J., Drew, P. J., & Costanzo, F. (2020) · Fluids and Barriers of the CNS · doi:10.1186/s12987-020-00214-3 · Cited by 70 · see citing works
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“This large ChP epithelial surface area provides unique opportunities for central nervous system (CNS) surveillance(17) and regulation of CSF volume and composition, based on mechanisms that control water and ion fluxes.(18,19) The ChP can be manipulated using adeno-associated virus (AAV)-based gene therapy.”
BackgroundResult
Na+‐K+‐2Cl−Cotransporter (NKCC) Physiological Function in Nonpolarized Cells and Transporting Epithelia
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“A manual search of this gene list revealed several transport proteins implicated in CSF secretion [38, 39] as upregulated in the choroid plexus of PHH rats compared to control rats (Table 1): Aquaporin 1 (AQP1), a water channel located at the luminal membrane of the choroid plexus, doubled in transcriptional abundance.”
Method
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“The choroid plexus has three roles: i) a barrier between blood and cerebrospinal fluid (CSF); ii) the major source of CSF production; and iii) a source of secreted soluble factors for the CSF (Damkier et al., 2013).”
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Cerebral spinal fluid dynamics: effect of hypoxia and implications for high-altitude illness
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“or NKCC1 AZE-dependent inhibition of carbonic anhydrases indirectly inhibits HCO3 transporters by reducing the available substrate, and most likely exerts its effect on CSF secretion by affecting some of these transport mechanisms located on both the sides of the CSF secreting choroid plexus epithelium [35].”
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NLRP3 inflammasome-mediated choroid plexus hypersecretion contributes to hydrocephalus after intraventricular hemorrhage via phosphorylated NKCC1 channels
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Ion Transport in the Choroid Plexus Epithelium
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Transport of ions across the choroid plexus epithelium
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Mechanisms of cerebrospinal fluid secretion by the choroid plexus epithelium: Application to various intracranial pathologies
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The structure of the choroid plexus and the physiology of the choroid plexus epithelium
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Cerebrospinal fluid production by the choroid plexus: a century of barrier research revisited
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Authors: Damkier, H. H., Brown, P. D., & Praetorius, J.
Affiliations: Aarhus University (DK)
Department of Biomedicine, Health, Aarhus University, Aarhus, Denmark; and Faculty of Life Sciences, Michael Smith Building, Manchester University, Manchester, United Kingdom
ORCID: Damkier, Helle H.
Brown, Peter D.
Venue: Physiological Reviews
Publisher: American Physiological Society
Published: 2013-10
Volume: 93
Issue: 4
Pages: 1847-1892
ISSN: 0031-9333 (ISSN-L)
1522-1210
DOI: 10.1152/physrev.00004.2013
OpenAlex: W2095851810
Cited by: 606
References: 364
Citations by year: 2026: 69 · 2025: 89 · 2024: 59 · 2023: 51 · 2022: 71 · 2021: 54 · 2020: 45 · 2019: 33 · 2018: 38 · 2017: 29 · 2016: 30 · 2015: 26 · 2014: 11 · 2013: 1
FWCI: 2.30
Type: journal article
Language: en
Open access: closed
Locations: Physiological Reviews (publishedVersion)
PubMed (publishedVersion)
Research Explorer (The University of Manchester) (publishedVersion)
Funders: Aarhus Universitet
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Keywords: choroid plexus, cerebrospinal fluid production, choroid plexus epithelium, ion transport, water transport, epithelial polarization, Alzheimer's disease, cerebral edema, hydrocephalus, choroid plexus tumors, aging
MeSH terms: Animals, Carrier Proteins, Cerebrospinal Fluid, Choroid Plexus, Humans, Water-Electrolyte Balance, Models, Animal

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Cerebrospinal fluid secretion by the choroid plexus

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