Molecular mechanisms of cerebrospinal fluid production

Abstract

The epithelial cells of the choroid plexuses secrete cerebrospinal fluid (CSF), by a process which involves the transport of Na + , Cl -and HCO 3 -from the blood to the ventricles of the brain. The unidirectional transport of ions is achieved due to the polarity of the epithelium, i.e. the ion transport proteins in the blood-facing (basolateral) membrane are different to those in the ventricular (apical) membrane. The movement of ions creates an osmotic gradient which drives the secretion of H 2 O. A variety of methods (e.g. isotope flux studies, electrophysiological, RT-PCR, in situ hybridization and immunocytochemistry) have been used to determine the expression of ion transporters and channels in the choroid plexus epithelium. Most of these transporters have now been localized to specific membranes. For example, Na + -K + ATPase, K + channels and Na + -2Cl --K + cotransporters are expressed in the apical membrane. By contrast the basolateral membrane contains Cl --HCO 3 exchangers, a variety of Na + coupled HCO 3 -transporters and K + -Cl -cotransporters. Aquaporin 1 mediates water transport at the apical membrane, but the route across the basolateral membrane is unknown. A model of CSF secretion by the mammalian choroid plexus is proposed which accommodates these proteins. The model also explains the mechanisms by which K + is transported from the CSF to the blood. Keywordschoroid plexus; blood-cerebrospinal fluid barrier; epithelial cells; ion transport; ion channels; Na + -K + ATPaseThe cerebrospinal fluid (CSF) is a major part of the extracellular fluid of the CNS. The CSF fills the ventricles of the brain, the spinal canal and the subarachnoid space ( Fig. 1), and in humans has a total volume of approximately 140 ml. The CSF is separated from neuronal tissue by the ependyma (which lines the ventricles and canals), and the pia (which covers the external surface of the brain). The composition of the CSF does, however, influence neuronal activity, notably in the central chemoreceptors of the medulla oblongata which control respiration by responding to changes in CSF pH.The CSF has a number of important functions. It helps provide mechanical support for the brain, i.e. the brain "floats" in the CSF reducing its effective weight by more than 60% (Segal, 1993). CSF also acts as a drainage pathway for the brain, by providing a "sink" into which products of metabolism or synaptic activity are diluted and subsequently removed * Corresponding author. Tel: +44-161-275-5463; fax: +44-161-275-5600. E-mail address: peter.d.brown@man.ac.uk (P. D. Brown).. Abbreviations:CFTRcystic fibrosis transmembrane conductance regulator CSF cerebrospinal fluid. Europe PMC Funders Group Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts (Segal, 1993). The CSF may also be an important route by which some nutrients reach the CNS . A final putative role for the CSF is that it acts as a route of communication within the CNS, i.e. it carries hormones and transmitters between different areas of the brain ....

The formation of cerebrospinal fluid: Nearly a hundred years of interpretations and misinterpretations

“…The secretory character of choroid plexuses that involves pumps, cotransporters and antiporters, ion channels and aquaporins has been confirmed during the past 15 years by the application of molecular biological methods (Brown et al, 2004;Johanson, 2008;Kanaka et al, 2001;Li et al, 2002;Oshio et al, 2005;Praetorius et al, 2004;Speake et al, 2003;Watts et al, 1991;Zlokovic et al, 1993).…”

“…The passage through the choroidal epithelium is an active metabolic process which transforms the ultrafiltrate into secretion (cerebrospinal fluid) (Brown et al, 2004;Davson et al, 1987;Johanson et al, 2008;Pollay et al, 1985;Segal and Pollay, 1977). Fluid secretion in epithelia has been found to be dependent on the unidirectional transport of ions, which creates an osmotic gradient inducing the movement of water (Figures 2, 3 and 4).…”

“…Based on literature (Bergsneider, 2001;Brodbelt and Stoodley, 2007;Brown et al, 2004;Davson et al, 1987;Johanson et al, 2008;Lyons and Meyer, 1990;Pollay 1977;Spector and Johanson, 1989), it could be generally shown that the net osmotic gradient across the choroid plexus is strictly regulated by the transport of Na + , Cl -, and HCO 3 -ions. The Na + /K + pump located on the CSFfacing (apical) membrane pumps Na + out of the choroid cells, driving down their intracellular Na + concentration (Figure 4).…”

“…Even if there were a dominant direction of active transport from the choroid plexus cell to the CSF, experiments on animals cannot reveal whether such transport has a sufficient capacity to form the volume of CSF that is predicted by the classic concept (Brown et al, 2004). Since even molecular research fails to give clear insight into net ionic transport towards CSF, it is difficult to accept the utmost active creation of CSF as an undoubted fact.…”

“…There is an assumption that the CSF is formed mainly by the secretory activity of choroid plexuses in the brain ventricles, and that the majority of the remaining CSF is probably produced by the ependyma (Brown et al, 2004;Davson et al, 1987;Johanson et al, 2008;McComb, 1983;O'Connel, 1970). It is generally accepted that CSF flows/circulates unidirectional from the brain ventricles to the subarachnoid space with the exchange of various substances (more or less manifested) between the CSF and interstitial compartments (Davson, 1967;Davson et al, 1987;Johanson et al, 2008;Plum and Siesjö, 1975).…”