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.
I have spent my career as an NINDS-funded neuroscientist developing expertise in neuronal ion homeostasis and translating my findings to clinical care. Although I have focused on seizure therapies, many of the discoveries I have made are equally applicable to the volume shifts that occur in neurons after brain injury. These volume shifts are among the most incalcitrant and problematic barriers to improved outcomes after brain injury. In the enclosed R35 application, I propose to leverage NINDS? investment in me and unravel these problems.
