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.