# Neuronal ion and volume shifts after acute brain injury

> **NIH NIH R35** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $609,032

## Abstract

The NINDS has provided me the opportunity to study neuronal ion homeostasis, GABA signaling, and
epileptogenesis for 30 years. That sustained support enabled the completion of a successful bench-to-
bedside translation of a new therapy for neonatal seizures, which are largely unresponsive to available
therapies. This new therapy is based on manipulation of neuronal anion homeostasis, which subserves
both GABAA receptor signaling and volume regulation. These studies led us to appreciate the magnitude of
the Donnan effects of intra and extracellular anionic macromolecules on neuronal chloride and volume
homeostasis. The delicate balance between intra and extracellular ionic and osmotic forces could be easily
upset by changes in membrane permeability or mobilization of osmoles on one side of the membrane. Here
we propose that brain injury results in both of these perturbations, with consequent catastrophic effects on
neuronal volume regulation. In the mature brain, this results in cytotoxic edema and brain swelling, for
which there are no curative and only modestly effective symptomatic therapies. In the premature brain,
volume changes are equally problematic, but our analyses predict that they are opposite in sign. We
propose that immature neurons shrink after injury, resulting in an absent MRI DWI signature as well as local
tissue shrinkage, vascular stretch, and potential hemorrhage. These effects contribute to the current
problems in the care of very low birthweight infants: brain injury is rampant, but the immediate causes are
not clear because the injury cannot be imaged with MRI or ultrasound. Only the consequences
(hemorrhage and atrophy) are visible. We propose to investigate neuronal ion and volume shifts after injury
in vitro and in vivo, using advanced imaging techniques and ion-sensitive fluorophores. The results will
provide robust indicators as to whether these new insights into volume shifts in injured neurons are ready
for translation to novel therapeutic strategies for both the developing and the mature injured brain.

## Key facts

- **NIH application ID:** 9986281
- **Project number:** 1R35NS116852-01
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Kevin J. Staley
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $609,032
- **Award type:** 1
- **Project period:** 2020-05-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9986281

## Citation

> US National Institutes of Health, RePORTER application 9986281, Neuronal ion and volume shifts after acute brain injury (1R35NS116852-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9986281. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*