The inner CSF–brain barrier: developmentally controlled access to the brain via intercellular junctions

Abstract

In the adult the interface between the cerebrospinal fluid and the brain is lined by the ependymal cells, which are joined by gap junctions. These intercellular connections do not provide a diffusional restrain between the two compartments. However, during development this interface, initially consisting of neuroepithelial cells and later radial glial cells, is characterized by “strap” junctions, which limit the exchange of different sized molecules between cerebrospinal fluid and the brain parenchyma. Here we provide a systematic study of permeability properties of this inner cerebrospinal fluid-brain barrier during mouse development from embryonic day, E17 until adult. Results show that at fetal stages exchange across this barrier is restricted to the smallest molecules (286Da) and the diffusional restraint is progressively removed as the brain develops. By postnatal day P20, molecules the size of plasma proteins (70 kDa) diffuse freely. Transcriptomic analysis of junctional proteins present in the cerebrospinal fluid-brain interface showed expression of adherens junctional proteins, actins, cadherins and catenins changing in a development manner consistent with the observed changes in the permeability studies. Gap junction proteins were only identified in the adult as was claudin-11. Immunohistochemistry was used to localize at the cellular level some of the adherens junctional proteins of genes identified from transcriptomic analysis. N-cadherin, β - and α-catenin immunoreactivity was detected outlining the inner CSF-brain interface from E16; most of these markers were not present in the adult ependyma. Claudin-5 was present in the apical-most part of radial glial cells and in endothelial cells in embryos, but only in endothelial cells including plexus endothelial cells in adults. Claudin-11 was only immunopositive in the adult, consistent with results obtained from transcriptomic analysis. These results provide information about physiological, molecular and morphological-related permeability changes occurring at the inner cerebrospinal fluid-brain barrier during brain development.

Functional antagonism of voltage-gated K+ channel α-subunits in the developing brain ventricular system

“…The latter function may be accomplished by the neuroepithelial barrier lining the ventricles (Chang et al, 2012;Fossan et al, 1985;Lowery and Sive, 2009;Whish et al, 2015). In the kcng4b morphant, this layer is compromised ( Fig.…”

“…It is thought that this is achieved by a combination of increased production of eCSF by neuroepithelial (ependymal) cells, which also function as neural stem cells (Desmond and Levitan, 2002;Johansson et al, 1999;Lowery and Sive, 2005;Mirzadeh et al, 2008;Meletis et al, 2008;Hamilton et al, 2009;Guo et al, 2011) and/or restriction of neuroepithelial permeability (Chang et al, 2012;Fossan et al, 1985;Lowery and Sive, 2009;Whish et al, 2015). While the mechanisms regulating the ventricular lining remain unclear, the expression of voltage-gated potassium (K v ) channels by ependymal cells might be essential due to their role in cell proliferation (Smith et al, 2008).…”

A balanced view of the cerebrospinal fluid composition and functions: Focus on adult humans

“…We will not discuss children less than two years of age because the functions, flow and reabsorption of CSF in their development are not yet fully studied (Bateman and Brown, 2012;Whish et al 2015). Also, due to the length consideration of this review, we do notcomprehensively treat spinal cord-CSF relationships and associated clinical problems,e.g.…”

“…Noteworthy is the fact that the blood-CSF barrier (BCSFB) consists of the CPepithelial cells and arachnoid membrane cells joined by tight junctions that inhibit the passive flux of H 2 O-soluble molecules (Spector et al, 2015). However, there is no appreciable barrier to diffusion between CSF and ECSB because the pial and ependymal linings contain gap junctions in animals and humans (Whish et al, 2015).In humans, the CSF volume is about 150 ml with ~20% residing in the lateral, third and fourth ventricles.…”

“…This diffusion occurs through permeable "gap" junctions (Whish et al 2015). However, there is now convincing human data that CSF flow is not unidirectionallysmooth like a river but there is bidirectional flow (oscillatory) through the aqueduct of Sylvius with the heart-beat, posture and especially inspiration (Table 2) (Dreha-Kulaczewski et al, 2015).…”