002. Ependymal Barrier Development in Relation to Periventricular Edema in CCDC39-Deficient Mouse Model of Neonatal Hydrocephalus

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Authors: Kylie Elizabeth Bachmann

Periventricular edema observed in severe neonatal hydrocephalus cases may exacerbate brain damage. However, the pathogenesis of the edema is largely conjecture. We challenged an existing hypothesis that physical disruption or malformation of the ependymal lining proceeds, and is therefore responsible for, periventricular edema formation in hydrocephalus.Methods: A genetic mouse model of severe progressive hydrocephalus (prh) with periventricular edema was used. Brain sections from wild-type and prh mutant mice, aged postnatal day (P)2 through 25 (total n = 30), were evaluated with immunohistochemistry to follow ependymal cell development and disruption in the normal and hydrocephalic brains.
In wild types, the vimentin+ ependymal cell lining developed incrementally from medial (P4) to lateral and dorsal (P8) walls of the lateral ventricles. A motile cilia protein, CCDC39, expression also represented the incremental ependymal cell maturation during the transition from GFAP+ radial glial cells to vimentin+ cuboidal cells. Astrocytic endfeet development under the basal side of ependymal layers was observed by P25. In the prh mutant, periventricular edema was first found in P4 prior to the physical denudation of ependymal cells, which was only seen from P8 on the lateral/dorsal walls (n=>2). Hypertrophic astrocytic gliosis was seen from P8, and disruption of radial glial cells and mature astrocytes was seen from P4. N-cadherin+ adherens junctions generally developed similarly in prh, up to the point of denudation or stratification.
Abnormal astrocyte development, but not ependymal denudation nor immaturity, preceded edema formation, suggesting that the astrocytic response may play a key role in regulating CSF absorption at the CSF-brain interface. Further investigation of the permeability of ependymal layer and astrocyte development will further elucidate the pathogenesis of periventricular edema in neonatal hydrocephalus.