Breakdown of Tight and Adherens Junctions Modulates the Choroid Plexus Intercellular Spaces After Intraventricular Hemorrhage
Riccardo Serra1, Bradley Wilhelmy1, Bosung Shim1, Vladimir Gerzanich1, J. Marc Simard2, Prajwal Ciryam3
1University of Maryland, 2University of Maryland Neurosurgery, 3University of Maryland School of Medicine
Objective:
We aim at describing the disruption in the choroid plexus (CP) blood-CSF barrier (BCSFB) ultrastructure caused by intraventricular hemorrhage (IVH).
Background:
In IVH, the CP epithelium drives cerebrospinal fluid (CSF) secretion. However, increases in CSF production do not explain variations in protein and cellular concentrations. The CP epithelium forms the BCSFB via intercellular tight and adherens junctions. The role of the paracellular pathway has never been explored in relation to shifts in CSF production.
Design/Methods:
A rodent model of autologous intraventricular hemorrhage was studied 6-, 24-, 48-hours, 7 days after initial induction. Intraventricular injection of normal saline was used as control. Immunohistochemistry, Western Blotting, electron microscopy were used to test the expression of claudin-1, N-cadherin and zonula adherens-1 (ZO-1).
Results:
A significant time-dependent reduction in claudin-1 and N-cadherin expression was noticed after 6-, 24- and 48hours. Intercellular junctions appeared intermittent or completely altered after IVH, with increased intra-cytoplasmic claudin-1 and N-cadherin signal. Partial reconstitution took place starting 48 hours after the injury and progressing through day 7. A significant difference between IVH and control was measured using adjusted mean fluorescence of claudin-1 and N-cadherin signal in the CP. ZO-1 ridges, an indirect intracellular marker of junctional integrity, were significantly reduced in length after 24 hours. Electron microscopy showed widening of the intercellular spaces (blebbing, local separation, reduction in length of junctions) 48 hours after IVH. Assessment of intercellular spaces in 50 images/group showed a significant difference between IVH and controls.
Conclusions:
The BCSFB is a complex structure formed by tight and adherens junctions of the CP. Breakdown of these structures after IVH has been demonstrated with immunohistochemistry, molecular techniques and electron microscopy. Changes in barrier function might explain the variability in protein content, ionic concentrations, water secretion, immune response, seen in animal models and IVH patient. Further characterization of their functional consequences is warranted.
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