Pharmacoresistant seizures and cytotoxic cerebral edema are serious complications of ischemic and traumatic brain injury. Intraneuronal Cl concentration ([Cl]) regulation impacts on both cell volume homeostasis and Cl-permeable GABA receptor-dependent membrane excitability. Understanding the pleiotropic molecular determinants of neuronal [Cl] - cytoplasmic impermeant anions, polyanionic extracellular matrix (ECM) glycoproteins, and plasmalemmal Cl transporters - could help the identification of novel anticonvulsive and neuroprotective targets. The cation/Cl cotransporters and ECM metalloproteinases may be particularly druggable targets for intervention. We establish here a paradigm that accounts for recent data regarding the complex regulatory mechanisms of neuronal [Cl] and how these mechanisms impact on neuronal volume and excitability. We propose approaches to modulate [Cl] that are relevant for two common clinical sequela of brain injury: edema and seizures.
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