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

> **NIH NIH R01** · STANFORD UNIVERSITY · 2024 · $673,189

## Abstract

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 ...

## Key facts

- **NIH application ID:** 10872934
- **Project number:** 1R01MH136258-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Ryan Marie Fame
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $673,189
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10872934

## Citation

> US National Institutes of Health, RePORTER application 10872934, How cerebrospinal fluid (CSF) potassium supports brain development and activity (1R01MH136258-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10872934. Licensed CC0.

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