How does mechanosensation contribute to choroid plexus function in health and disease? - Project Summary The choroid plexus is a structure that extends from the walls of the brain’s four ventricles, floating in the cerebrospinal fluid (CSF). It is thought to be the source of CSF and thus play a role in controlling the content and volume of the fluid that bathes the brain and spinal cord. However, it is unknown whether the choroid plexus can sense CSF flow or hydrostatic pressure in the ventricles and how it might use this information to modulate CSF production. The combination of CSF, brain, and blood volumes determine intracranial pressure (ICP), and changes in one of these parameters typically leads to compensatory changes in one or both of the other two. In the absence of these compensatory mechanisms, ICP can increase past the normal range, leading to headaches, seizures, neural damage, and in extreme cases, death. Pathological ICP levels occur in several neurological injuries and diseases (traumatic brain injury, stroke, hemorrhage, tumor, hydrocephalus, and during seizures). Thus, understanding the mechanisms underlying ICP sensation and compensation could inform therapeutic strategies for handling dysregulated ICP across multiple neuropathologies. This proposal aims to investigate mechanosensation at the choroid plexus with the overarching goal of understanding ICP dynamics in health and disease. PIEZO1 is a cation channel activated by mechanical stimuli. It is expressed in choroid plexus epithelial cells (CPECs), the cell type thought to be responsible for CSF production, but its role there is entirely unknown. Remarkably, I found that conditional knockout of Piezo1 from CPECs increases seizure susceptibility in mice in the context of kainic acid-induced neuronal hyperactivity. This proposal will test what stimuli activate PIEZO1 in CPECs and how this signal might be used to regulate and stabilize ICP. More specifically, I will use electrophysiology and calcium imaging in primary cell culture and choroid plexus explants to characterize PIEZO1 activity in CPECs. I will also assess ICP dynamics after manipulation of CSF volume and neuronal activity in control mice and those lacking Piezo1 in CPECs. Finally, I will explore the downstream effects of activating PIEZO1 in CPECs, and I will test whether increasing CSF clearance at the choroid plexus might ameliorate seizure severity in the absence of choroid plexus PIEZO1. Together, the results from these experiments will contribute to our understanding of how the choroid plexus senses and regulates ICP. This knowledge could help inform how ICP dysregulation is treated in the context of neurological diseases including stroke and traumatic brain injury.
