Optogenetic countering of glial acidosis suppresses glial glutamate release and ischemic brain damage

Neuron. 2014 Jan 22;81(2):314-20. doi: 10.1016/j.neuron.2013.11.011.


The brain demands high-energy supply and obstruction of blood flow causes rapid deterioration of the healthiness of brain cells. Two major events occur upon ischemia: acidosis and liberation of excess glutamate, which leads to excitotoxicity. However, cellular source of glutamate and its release mechanism upon ischemia remained unknown. Here we show a causal relationship between glial acidosis and neuronal excitotoxicity. As the major cation that flows through channelrhodopsin-2 (ChR2) is proton, this could be regarded as an optogenetic tool for instant intracellular acidification. Optical activation of ChR2 expressed in glial cells led to glial acidification and to release of glutamate. On the other hand, glial alkalization via optogenetic activation of a proton pump, archaerhodopsin (ArchT), led to cessation of glutamate release and to the relief of ischemic brain damage in vivo. Our results suggest that controlling glial pH may be an effective therapeutic strategy for intervention of ischemic brain damage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acidosis* / etiology
  • Acidosis* / metabolism
  • Acidosis* / pathology
  • Animals
  • Animals, Newborn
  • Archaeal Proteins / genetics
  • Archaeal Proteins / metabolism
  • Cerebellum / drug effects
  • Cerebellum / metabolism
  • Channelrhodopsins
  • Disease Models, Animal
  • Excitatory Amino Acid Antagonists / pharmacology
  • Glucose / deficiency
  • Glutamic Acid / metabolism*
  • Hypoxia / pathology
  • Hypoxia-Ischemia, Brain / complications*
  • In Vitro Techniques
  • Membrane Potentials / drug effects
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Transgenic
  • Microscopy, Immunoelectron
  • Neuroglia / metabolism*
  • Neuroglia / ultrastructure
  • Optogenetics*
  • Sodium Channel Blockers / pharmacology
  • Vesicular Acetylcholine Transport Proteins


  • Archaeal Proteins
  • Channelrhodopsins
  • Excitatory Amino Acid Antagonists
  • Membrane Proteins
  • Mlc1 protein, mouse
  • Sodium Channel Blockers
  • Vesicular Acetylcholine Transport Proteins
  • archaerhodopsin protein, Archaea
  • Glutamic Acid
  • Glucose