How cerebrospinal fluid (CSF) potassium supports brain development and activity

PROJECT SUMMARY/ ABSTRACT The brain and spinal cord are filled with and surrounded by a complex fluid, the cerebrospinal fluid (CSF). CSF directly contacts brain progenitors to act as a stem cell niche that provides buoyancy, ionic and osmotic balance, and health- and growth- promoting factors. Pathological deviations in CSF volume and composition are associated with congenital, neuropsychiatric, infectious, and geriatric diseases, as well as injury. As the brain matures during development, CSF composition changes profoundly. We recently discovered that CSF ion concentrations also change dramatically across development, including a ~2.5-fold drop in CSF [K+] during the first postnatal week in rodents (from ~10 mM to ~3.2 mM). This large natural shift in CSF [K+] has the potential to affect key processes in brain development including progenitor maintenance, neurogenesis, and physiology. Our lab has the tools and expertise to directly control CSF [K+] and assess neurodevelopmental outcomes. Extracellular K+ is a fundamental signal for proliferation, survival, and cellular migration. K+ is also a key ion regulating cellular physiology, excitability, and ion co-transport. It is therefore crucial to understand how developmentally dynamic CSF ions contribute to brain generation and maturation. A major tissue source of CSF ions is the choroid plexus. We found that choroid plexus-restricted knockdown or overexpression of the sodium- potassium-chloride cotransporter NKCC1 (Slc12a2) delays or accelerates the drop in CSF [K+], respectively. It is now possible to directly test hypotheses that stage-specific CSF ions support neural progenitors and immature neurons to drive long-term brain function. Here, we propose to answer fundamental, yet transformative questions of whether CSF ions are necessary and sufficient to support brain development. Here we adapt explant manipulation and in vivo AAV gene delivery to investigate how the higher [K+] that we observe in early CSF specifically supports early neurodevelopment (aim 1); how the lower [K+] that we observed in postnatal CSF specifically supports neural maturation (aim 2); and test whether the shift in CSF [K+] alters the Cl- and K+ shunting that occurs as part of the developmental GABA switch (aim 3). This multi-tiered approach will yield widely applicable information and tools for testing hypotheses of CSF ion function over development, and in health and disease. Each component builds on my unique expertise to facilitate a new research program investigating how CSF supports the maturation of neurons and circuits underlying psychiatric disease. This innovative research program will fundamentally change our understanding of brain development and reveal roles for CSF ions in supporting brain generation and physiology. The CSF is an accessible avenue for CNS surveillance or supplementation, even in humans (e.g. intranasal spray, intrathecal injections). Therefore, outcomes will guide efforts to harness CSF to provide a supportive developmental environment for the brain, reduce neurologic symptoms, and may provide therapeutic strategies for tackling a range of disease.