Ablation of the choroid plexus attenuates hydrocephalus-induced parenchymal edema with moderate reduction of postnatal hippocampal neurogenesis

Choroid plexus (ChP) produces cerebrospinal fluid (CSF) and regulates brain development and adult subventricular zone (SVZ) neurogenesis, but its role in postnatal hippocampal subgranular zone (SGZ) neurogenesis is not well understood. Infantile hydrocephalus is sometimes treated with lateral ventricle ChP cauterization, which often improves clinical symptoms without substantially reducing ventricular volumes. To understand the roles of the ChP/CSF system in normal conditions and the impact of ChP ablation or cauterization in hydrocephalus, novel tools for the manipulation of ChP-mediated CSF production are urgently needed. We first tested the ROSA26-iDTR mouse model for ChP ablation at neonatal ages, then generated a novel AAV5-CMV-DTR vector with high ChP tropism to effectively reduce ventricular volume in neonatal mice. Genetic and gene therapy approaches were compared for their extent of ChP ablation, reduction of ventricular CSF volume assessed by MRI, and impact on postnatal hippocampal neurogenesis in neonates and adults. Lastly, we tested AAV-mediated ChP ablation in a kaolin model of hydrocephalus. In ROSA26-iDTR mice, ChP ablation and CSF volume reduction were robust at postnatal day (P)10–12, but ineffective at P3-5 with standard diphtheria toxin (Dtx) dosing (20 ng/g/day, 3 consecutive days). A higher dose (40 ng/g/day) at P3-5 mildly reduced CSF but caused neonatal mortality. In contrast, AAV5-CMV-DTR showed high tropism for ChP epithelium, producing a marked reduction in ventricular CSF in neonates. ChP/CSF loss in neonatal or adult mice substantially reduced neuroblasts within the SVZ, but only moderately so in the SGZ, without altering the number of proliferating or apoptotic cells. In the kaolin model, AAV-mediated ChP ablation initiated within 10 hrs after hydrocephalus induction profoundly reduced parenchymal edema and corpus callosum hyperintensity without causing ventricular collapse. We demonstrate a role of the ChP/CSF in maintaining the neuroblast pool in both postnatal neurogenic niches. Because ROSA26-iDTR-mediated ChP ablation is inefficient before P10, the alternative AAV5-DTR approach is relevant for both neonatal and adult ages, and is shown to be feasible for the treatment of acquired hydrocephalus. The radiographic changes in the kaolin mouse model parallels the radiographic responses reported after choroid plexus cauterization in children.