Timing of Neuronal Chloride Uptake for Control of Neonatal Seizure

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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.