Ependymal Dysfunction Links Ventricular Enlargement to Neuroinflammation: Implications for Hydrocephalus and Neurodegeneration

Abstract Hydrocephalus is often associated with motile ciliary dysfunction in mice. It is believed that ependymal ciliary abnormalities impede cerebrospinal fluid (CSF) circulation, resulting in increased intracranial pressure. We previously identified Hoatz as a cilia-related gene and demonstrated that knockout mice develop ventriculomegaly. In this study, we combined in vivo magnetic resonance imaging (MRI), transcriptomics, and histology to elucidate the potential mechanisms underlying ventricular enlargement. High-resolution T₂-weighted MRI revealed a ~ 4.5-fold increase in ventricular volume, occasionally accompanied by edematous fluid accumulation in the corpus callosum. However, the overall brain size was preserved, indicating parenchymal atrophy rather than simple intracranial hypertension. Unexpectedly, transcriptome profiling of ependymal cultures revealed robust upregulation of microglia-associated genes. Immunostaining confirmed activation of coexisting microglia, regardless of intracranial pressure. Similarly, RNA sequencing (RNA-seq) of hippocampal tissues identified multiple upregulated genes, enriched in immune-related pathways, including Trem2, Tyrobp, C1qa/b, Lyz2, and Ctss. Furthermore, confocal imaging revealed an amoeboid, activated morphology of hippocampal microglia. These findings indicate that ventriculomegaly in Hoatz-null mice may result not only from impaired CSF flow but also from neuroinflammation-driven neurodegeneration. This dual mechanism suggests potential relevance to normal pressure hydrocephalus and other neurodegenerative disorders.