Choroid Plexus Ablation Eases Hydrocephalus Brain Swelling in Mice

Ablating the choroid plexus, the tissue inside the brain’s ventricles that produces cerebrospinal fluid, sharply reduced the parenchymal edema that develops after experimentally induced hydrocephalus in adult mice, according to a new study published in Fluids and Barriers of the CNS. The intervention, delivered through a viral gene therapy vector, did not shrink the enlarged ventricles themselves but prevented the white matter swelling that expands in untreated animals, offering a proof of principle for a minimally invasive strategy against a devastating neurological disorder.

The research team, led by Aleksandr Taranov and Yu Luo, also mapped how losing the choroid plexus and its cerebrospinal fluid affects the brain’s two postnatal neurogenic niches. In both adolescent and neonatal mice, depletion of the fluid substantially reduced neuroblasts in the subventricular zone lining the lateral ventricles, while the subgranular zone of the hippocampus showed only a moderate reduction. Neither proliferating Ki67-positive cells nor TUNEL-positive apoptotic cells differed between ablated and control animals, suggesting the fluid supports the differentiation, maturation or survival of newly born neuroblasts rather than the proliferation of neural stem cells.

Hydrocephalus involves excessive accumulation of cerebrospinal fluid, usually from impaired drainage caused by congenital abnormalities or injuries such as infection, head trauma or hemorrhage, and less commonly from overproduction. The resulting ventricular expansion compresses surrounding brain tissue and is often accompanied by periventricular T2 signal change on magnetic resonance imaging, an appearance indistinguishable from parenchymal edema that is associated with white matter demyelination, axonal injury and neuroinflammatory gliosis. Current surgical options, including choroid plexus cauterization, endoscopic third ventriculostomy and cerebrospinal fluid shunting, carry high rates of complications, motivating the search for one-time, minimally invasive treatments.

To manipulate the choroid plexus, the researchers first tested the ROSA26-iDTR mouse line, in which choroid plexus epithelial cells unexpectedly express the diphtheria toxin receptor independently of Cre recombinase, making them vulnerable to diphtheria toxin-mediated cell death. In adolescent mice treated at one month of age with 20 nanograms per gram of toxin daily for three days, ablation was robust, and ventricular cerebrospinal fluid volume fell by more than 90 percent. When the same regimen was applied at postnatal days 3 to 5, however, it failed to reduce ventricular volume, and doubling the dose produced only modest fluid reduction while causing considerable neonatal mortality by postnatal day 15 in both mutant and wild-type pups.

The age dependence proved instructive. Treatment beginning at postnatal days 10 to 12 achieved fluid loss comparable to that seen in adults, indicating that the leaky receptor expression in the choroid plexus is developmentally regulated and insufficient before roughly postnatal day 10. Because infantile hydrocephalus is sometimes treated with choroid plexus cauterization in children under one year, the team needed a tool that works in the earliest postnatal period. They therefore engineered a novel AAV5-CMV-DTR vector, exploiting the known tropism of adeno-associated virus serotype 5 for choroid plexus epithelium.

Injected unilaterally into the lateral ventricle of postnatal day 1 pups, a reporter version of the vector transduced more than 70 percent of transthyretin-positive epithelial cells across the lateral, third and fourth ventricle plexuses, with only sparse expression outside the choroid plexus and none in adjacent ependymal, hippocampal or cortical tissue. The therapeutic vector produced similar results in young adult mice. When combined with systemic diphtheria toxin given on postnatal days 4 to 6, the vector caused substantial loss of choroid plexus tissue and a profound, stable reduction in ventricular cerebrospinal fluid measured by magnetic resonance imaging at postnatal days 21 and 30, matching the effect of the genetic model in older animals.

The neonatal ablation experiments yielded a nuanced picture of neurogenesis. In the subventricular zone, whole-mount preparations revealed a marked decrease in doublecortin-positive neuroblasts and a striking change in their organization: instead of the expected net-like migratory network, ablated animals showed isolated clusters of neuroblasts, with ependymal cells reorganized around these clusters even though ependymal coverage was not lost. In the hippocampal subgranular zone, the decrease in doublecortin-positive cells was moderate, and hippocampal volume as well as total brain volume were significantly reduced. Open field testing at postnatal day 30 showed a mild reduction in novelty-induced horizontal activity, movement time, vertical activity and stereotypic behavior without changes in average speed or body weight, hinting at subtle behavioral consequences of neonatal ablation.

The therapeutic test used the kaolin model, a well-established hydrocephalus paradigm in which kaolin injected into the cisterna magna triggers inflammation that obstructs cerebrospinal fluid flow and absorption, producing progressive ventriculomegaly and elevated intracranial pressure. Adult mice received the DTR or control vector, hydrocephalus was induced ten days later, and diphtheria toxin was started just 6 to 10 hours after kaolin injection. Magnetic resonance imaging on days 4 and 7 showed that in control animals, parenchymal edema and corpus callosum hyperintensity expanded substantially between the two time points, whereas in choroid plexus-ablated mice the edema was profoundly reduced and did not expand, all without reducing ventriculomegaly or causing ventricular collapse.

The authors note that the radiographic changes in the kaolin model parallel the responses reported after choroid plexus cauterization in children, a procedure that often improves clinical symptoms without substantially reducing ventricular volumes. In their experiment, a survival analysis based on predefined humane endpoints showed a median survival of 8 days for control-treated hydrocephalic mice versus 13 days for ablated mice, but the authors caution that with the small sample size and the fact that not all deaths were natural, no statistically significant conclusion about survival can be drawn. They also emphasize that hydrocephalus is dynamic: once secondary events such as white matter injury, neuroinflammation, axonal damage and barrier disruption are initiated, reducing fluid production may no longer reverse tissue injury, so future work must compare early and late ablation.

Several limitations frame the findings. The analyses of subgranular zone proliferation and apoptosis relied on single time points and could have missed transient changes, no direct cognitive testing was performed, and the study did not examine cerebrospinal fluid composition or blood-cerebrospinal fluid barrier properties after ablation. Whether AAV5 or other serotypes show comparable tropism and efficiency in human choroid plexus epithelium remains to be investigated. The authors also speculate that the modest hippocampal effect, compared with the pronounced subventricular zone phenotype, reflects the subgranular zone’s greater distance from ventricular cerebrospinal fluid and its distinct migratory geography. Still, the study establishes complementary tools, the ROSA26-iDTR model for late juvenile and adult stages and the AAV5-DTR vector for neonatal and adult stages, and demonstrates a role for the choroid plexus and its fluid in maintaining the neuroblast pool in both postnatal neurogenic niches while pointing toward gene therapy as a potential strategy for disorders of cerebrospinal fluid homeostasis.

Subject of Research: Choroid plexus ablation via AAV5 gene therapy reduces hydrocephalus-induced brain edema and affects postnatal neurogenesis in mice

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

Article References: Taranov, A., Mayrhofer, F., Hamm, S., Kniffen, E., Peter, J., Wallace, F., Lullmann, O., McClain, L., Chechneva, O. V., Sadegh, C., & Luo, Y. (2026). Ablation of the choroid plexus attenuates hydrocephalus-induced parenchymal edema with moderate reduction of postnatal hippocampal neurogenesis. Fluids and Barriers of the CNS, 23(1), Article 115. https://doi.org/10.1186/s12987-026-00882-7

Image Credits: AI Generated

DOI: 10.1186/s12987-026-00882-7

Keywords: choroid plexus, hydrocephalus, cerebrospinal fluid, AAV5 gene therapy, neurogenesis, hippocampus, subventricular zone, kaolin model, parenchymal edema, diphtheria toxin receptor, MRI, mouse study