Ablating choroid plexus epithelial cells in the developing mouse brain: A new tool to approach CSF disorders

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Project Summary The choroid plexus (CP) and cerebral spinal fluid (CSF) system serve multiple active roles in regulating brain formation and the brain's overall health. Emerging new knowledge is determining catalogs of molecules in the CP-CSF system and their role in brain development as well as an immune-brain interaction. Dysregulation of CSF production or circulation causes diseases such as hydrocephalus, and CP atrophy has been observed in multiple CNS disorders. These observations in the human brain disorders indicate that the CP-CSF system has engaged roles in the brain disease progression or exacerbation. There is rising interest in CP-targeted therapies in CSF volume and neuroinflammation management. In fact, recently, clinical benefits of CP coagulation in endoscopic third ventriculostomy treatment have been demonstrated in the treatment of pediatric hydrocephalus patients in developing countries. However, contrary to its important roles, the CP- CSF system has mainly been remained an under-explored field in neuroscience due to limitations in the number of available tools to precisely modulate its functions. The NIH Funding Opportunity PA-21-219 " The Joint NINDS/NIMH Exploratory Neuroscience Research Grant program" recognizes the unmet need for "novel tools or models that have the potential to bring breakthroughs to the neuroscience community." By using a novel transgenic mouse line that we recently discovered, our project will address the goals by (1) establishing a new tool to ablate CP in mice and (2) modeling hydrocephalus brains with CP-targeted treatment. Our rigorous preliminary data indicated that (1) this line can induce exclusive apoptotic cell death only in the CP epithelial cells and (2) the CP ablation results in partial to near-complete 50-90% reduction in ventricular volume depending on the dose and timing of agent administration. We will characterize the dosing effects and investigate the positive and potential adverse effects of partial and near-complete CP ablation in hydrocephalus and otherwise healthy brain development. Our comprehensive MRI, intracranial pressure, gene expression, cytokine profiling, and immunohistochemical characterization will reveal the effects of this new tool on intracranial pressure, ventricle size, CP regeneration capacity, and postnatal neurodevelopment. This will broaden our fundamental understanding of the function of CP and CSF in perinatal brain development. In addition, our needs-based tools will be important in clarifying the key role of the CP-CSF system in the pathogenesis and treatment of hydrocephalus. This project provides an essential platform for elucidating the role of CP-CSF in underlying brain development and function. By establishing a new tool to remove CP-CSF in mice at any desired timepoints (neonatal to adulthood), our project will make significant contributions and impact on promoting studies of the CP-CSF system in a wide range of topics in neuroscience and brain diseases.