Neonatal diphtheria toxin treatment of iDTR mice reduces ventricular volume and shows damage in the choroid plexus in an age-dependent manner

This is the authors' abstract. We don't add key points for this paper.

The choroid plexus (ChP), which is located in the cerebral ventricles, is the principal source of cerebrospinal fluid (CSF), contributing to approximately 80% of its production. Dysregulation of CSF volume results in neonatal hydrocephalus, a condition with an estimated incidence of 0.1–0.6% in children. Current treatments for neonatal hydrocephalus are invasive and carry high risks of complications and multiple surgical interventions, underscoring the need for alternative strategies, such as targeting CSF production. Previously, we showed that diphtheria toxin (Dtx) induces ChP epithelial loss and permanent CSF volume loss in adult iDTR mice, whereas ChP/CSF removal in the neonatal brain remains unexplored. Here, we investigate the impact of ChP ablation and subsequent CSF reduction at early postnatal stages in iDTR mice. We describe that multiple Dtx injections between P4 and P6, or a single injection at P10, significantly reduce ventricular volume at P30, whereas single injections before P8 have no effect. Moreover, histological and gene expression analyses revealed age-dependent disruption of epithelial cells, an increase in ChP epithelial cell death, long-term changes in ChP gene expression patterns, and a significant reduction in total ChP size. Furthermore, early postnatal ChP epithelial loss reduced ventricular volume in the prh neonatal hydrocephalus mouse model. These findings highlight the clinical feasibility of long-term CSF volume control via ChP removal in the developing brain, supporting the clinical potential of ChP-ablation therapies for neonatal hydrocephalus.