Reduced subcommissural organ glycoprotein immunoreactivity precedes aqueduct closure and ventricular dilatation in H-Tx rat hydrocephalus

Abstract

The H-Tx rat has fetal-onset hydrocephalus associated with closure of the cerebral aqueduct and a reduction in the secretory cells of the subcommissural organ (SCO), a circumventricular organ situated in the dorsal wall of the cerebral aqueduct. The objective of this study was to determine the role of the SCO in hydrocephalus pathogenesis. Serial brain sections through aqueduct regions containing the SCO from H-Tx rats, together with non-hydrocephalic Fischer F344 rats, were studied at E16, before hydrocephalus onset, at E17, the beginning of onset, and at P0 when the hydrocephalus was overt. Tissues were immunostained by AFRU, an antibody against the SCO glycoprotein, and for the intermediate filament nestin. The area of SCO cells with AFRU immunostaining and the severity of lateral ventricle dilatation were quantified by image analysis. At E16 all fetuses had distinct SCO ependymal cells, open aqueducts and normal lateral ventricles. The H-Tx fetuses fell into two groups with large areas and small areas of AFRU immunoreactivity, all with a full complement of SCO cells. By E17, fetuses with small areas of immunoreactivity had reduced numbers of tall SCO secretory cells, and most had aqueducts closed posteriorly and dilated ventricles. Three additional fetuses with small areas of immunoreactivity had narrow but patent aqueducts and normal ventricles, and another had an open aqueduct and dilated ventricles. At P0, pups previously identified as hydrocephalic had small areas of AFRU immunoreactivity, an aqueduct that was closed anteriorly but open posteriorly, ventricular dilatation, and an absence of SCO secretory cells. The aqueduct even when closed was lined by typical ependymal cells throughout. Decreased nestin immunostaining accompanied the SCO changes. It is concluded that reduced SCO glycoprotein immunoreactivity precedes both aqueduct closure and expansion of the lateral ventricles in the H-Tx rat.

Single and multiple congenic strains for hydrocephalus in the H-Tx rat

“…The initial events in the brain that lead to hydrocephalus are not well understood. Recently, however, it was demonstrated that ventricular dilatation is preceded by underdevelopment of the subcommissural organ (SCO), an ependymal secretory gland in the dorsal cerebral aqueduct, and is associated with a reduction in immunostaining of the secretory glycoprotein (Somera and Jones 2004). This is consistent with other evidence for a link between SCO function and hydrocephalus in that many animal models have an SCO deficiency (Pérez-Fígares et al 2001).…”

“…Histological examination of brains-In a previous study it was shown that H-Tx pups with potentially severe hydrocephalus at 0-1 days of age have an abnormal cerebral aqueduct and hypoplasia of the subcommissural organ, whereas H-Tx pups without ventricular dilatation and Fischer F344 pups do not have these features (Somera and Jones 2004). In this study, C10, C11, and C17 congenic rats all appeared to be completely normal when compared to the same region in F344 rats.…”

“…In the H-Tx rat the onset of ventricular dilatation occurs at 17-18 days gestation and is associated with an abnormal cerebral aqueduct (Jones and Bucknall 1988). It was shown recently, however, that at 17 days gestation ventricular dilatation can occur without aqueduct obstruction and that reduction in the immunoreactivity of the glycoprotein in the subcommissural organ precedes both ventricular expansion and aqueduct closure (Somera and Jones 2004). This suggests that the pathogenesis is more complex than obstruction of the CSF through aqueduct closure.…”

“…The aqueduct was examined for signs of narrowing or nonpatency and the dorsal regions, including the SCO, were studied for immunostaining. Quantification of the immunostained areas was performed on the brains of four rats from each strain, and ventricular dilatation was measured on sections of cerebral cortex as described previously (Somera and Jones 2004). The brains from nonhydrocephalic Fischer F344 pups were used as controls for the congenic strains.…”

Neuropathological Changes in Hydrocephalus—A Comprehensive Review

“…In regards to its main function, CSF overproduction by the choroid plexus is a rare a cause of hydrocephalus [3] [8] [241]. [252] and exhibits decreased glycoprotein immunoreactivity [253], and the subfornical organ can become damaged as the condition progresses [254].…”