Optogenetic countering of glial acidosis suppresses glial glutamate release and ischemic brain damage.
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.
Division of Cerebral Structure, National Institute for Physiological Sciences, Graduate University for Advanced Studies (SOKENDAI), Okazaki 444-8787, Japan; Department of Physiological Sciences, Graduate University for Advanced Studies (SOKENDAI), Okazaki 444-8787, Japan.
Kaoru
K
Beppu
Division of Cerebral Structure, National Institute for Physiological Sciences, Graduate University for Advanced Studies (SOKENDAI), Okazaki 444-8787, Japan.
Takuya
T
Sasaki
Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo 160-8582, Japan.
Kenji F
KF
Tanaka
Department of Neuroscience II, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan.
Akihiro
A
Yamanaka
Department of Anatomy and Molecular Cell Biology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
Yugo
Y
Fukazawa
Division of Cerebral Structure, National Institute for Physiological Sciences, Graduate University for Advanced Studies (SOKENDAI), Okazaki 444-8787, Japan; Department of Physiological Sciences, Graduate University for Advanced Studies (SOKENDAI), Okazaki 444-8787, Japan; IST Austria, 3400 Klosterneuburg, Austria.
Ryuichi
R
Shigemoto
Division of Cerebral Structure, National Institute for Physiological Sciences, Graduate University for Advanced Studies (SOKENDAI), Okazaki 444-8787, Japan; Department of Physiological Sciences, Graduate University for Advanced Studies (SOKENDAI), Okazaki 444-8787, Japan; Division of Interdisciplinary Medical Science, Center for Neuroscience, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan. Electronic address: matsui@med.tohoku.ac.jp.
Ko
K
Matsui
D000138:Acidosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000831:Animals, Newborn; D019843:Archaeal Proteins / Q000235:genetics / Q000378:metabolism; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D000075402:Channelrhodopsins; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005947:Glucose / Q000172:deficiency; D018698:Glutamic Acid / Q000378:metabolism*; D000860:Hypoxia / Q000473:pathology; D020925:Hypoxia-Ischemia, Brain / Q000150:complications*; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D016253:Microscopy, Immunoelectron; D009457:Neuroglia / Q000378:metabolism* / Q000648:ultrastructure; D062308:Optogenetics; D026941:Sodium Channel Blockers / Q000494:pharmacology; D050494:Vesicular Acetylcholine Transport Proteins; D017494:Proton Pumps
D019843:Archaeal Proteins; D000075402:Channelrhodopsins; D018691:Excitatory Amino Acid Antagonists; D005947:Glucose; D018698:Glutamic Acid; D008565:Membrane Proteins; D026941:Sodium Channel Blockers; D050494:Vesicular Acetylcholine Transport Proteins; C498927:Mlc1 protein, mouse; C055476:archaerhodopsin protein, Archaea; D017494:Proton Pumps