# Timing of neuronal chloride uptake for control of neonatal seizure

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $403,000

## Abstract

Project Summary and Abstract
Neuronal chloride concentration ([Cl-]i) is an important determinant of both post-synaptic GABAA-
receptor mediated signaling and cell volume regulation. After injury, neurons swell by admitting water
and chloride salts. The chloride moiety alters the reversal potential for GABA signaling, compromising
inhibition and contributing to early anticonvulsant-resistant seizures that are thought to worsen long-
term outcomes. An important pathway for neuronal entry of water and chloride salts are the reversible
cation-Cl- cotransporters (CCC) NKCC1 and KCC2. We hypothesize that emergent limitation of
neuronal chloride influx after recovery from hypoxia-ischemia by antagonizing NKCC1 activity and/or
KCC2 activity is a uniquely effective therapeutic strategy to reduce acute cell swelling and [Cl-]i
elevation in injured neurons, restore GABAergic inhibition, prevent chronic [Cl-]i elevation, recurrent
seizures and epileptogenesis. We will test these hypotheses in vitro and in vivo using established
models of hypoxic ischemic injury, transgenic chloride imaging, and multiphoton microscopy. The
overall goal of this project is to elucidate the progressive role of cation-chloride transport activity in
hypoxia-ischemia induced neuronal injury and seizures. The results will have an important positive
impact immediately because they will identify an optimal therapeutic window for prevention and
treatment of recurrent seizures in newborns that have suffered hypoxia-ischemia and are at high risk
for developing anticonvulsant resistant seizures, epilepsy, cerebral palsy and neuromotor disabilities.

## Key facts

- **NIH application ID:** 10360082
- **Project number:** 1R01NS120973-01A1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Volodymyr Dzhala
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $403,000
- **Award type:** 1
- **Project period:** 2022-01-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10360082

## Citation

> US National Institutes of Health, RePORTER application 10360082, Timing of neuronal chloride uptake for control of neonatal seizure (1R01NS120973-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10360082. Licensed CC0.

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