Chloride Dysregulation, Seizures, and Cerebral Edema: A Relationship with Therapeutic Potential

Trends Neurosci. 2017 May;40(5):276-294. doi: 10.1016/j.tins.2017.03.006. Epub 2017 Apr 18.


Pharmacoresistant seizures and cytotoxic cerebral edema are serious complications of ischemic and traumatic brain injury. Intraneuronal Cl- concentration ([Cl-]i) regulation impacts on both cell volume homeostasis and Cl--permeable GABAA receptor-dependent membrane excitability. Understanding the pleiotropic molecular determinants of neuronal [Cl-]i - 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-]i and how these mechanisms impact on neuronal volume and excitability. We propose approaches to modulate [Cl-]i that are relevant for two common clinical sequela of brain injury: edema and seizures.

Keywords: GABA; KCC2; NKCC1; brain development; cerebral edema; chloride; extracellular matrix; inhibition; seizures; traumatic brain injury.

Publication types

  • Review
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Edema / metabolism*
  • Brain Injuries, Traumatic / metabolism*
  • Chlorides / metabolism*
  • Extracellular Matrix / metabolism*
  • Humans
  • Neurons / metabolism*
  • Seizures / metabolism*
  • Symporters / metabolism*


  • Chlorides
  • Symporters