title: Astrocytic Ca(2+) waves mediate activation of extrasynaptic NMDA receptors in hippocampal neurons to aggravate brain damage during ischemia.
abstract: Excitotoxicity plays a central role in the neuronal damage during ischemic stroke. Although growing evidence suggests that activation of extrasynaptic NMDA receptors initiates neuronal death, no direct evidence demonstrated their activation during ischemia. Using rat hippocampal slices, we detected oxygen-glucose deprivation (OGD) induced slow inward currents (SICs) mediated by extrasynaptic NMDA receptors in CA1 pyramidal neurons. Moreover, Ca(2+) chelator BAPTA dialysis into astrocytic network decreased the frequency of OGD induced SICs, indicating that the activation of extrasynaptic NMDA receptors depended on astrocytic Ca(2+) activity. To further demonstrate the importance of astrocytic Ca(2+) activity, we tested hippocampal slices from inositol triphosphate receptor type 2 (IP3R2) knock-out mice which abolished the astrocytic Ca(2+) activity. As expected, the frequency of OGD induced SICs was reduced. Using two-photon Ca(2+) imaging, we characterized the astrocytic Ca(2+) dynamics. By controlling Ca(2+) level in the individual astrocytes using targeted photolysis, we found that OGD facilitated the propagation of intercellular Ca(2+) waves, which were inhibited by gap junction blocker carbenoxolone (CBX). CBX also inhibited the Ca(2+) activity of the astrocytic network and decreased the SIC frequency during OGD. Functionally, the infarct volumes from brain ischemia were reduced in IP3R2 knock-out mice and in rat intracerebrally delivered with CBX. Our results demonstrate that enhanced Ca(2+) activity of the astrocytic network plays a key role on the activation of extrasynaptic NMDA receptors in hippocampal neurons, which enhances brain damage during ischemia.
authors.affiliation: College of Life Sciences, Peking University, Beijing, China.
authors.forename: Qi-Ping
authors.initials: QP
authors.lastname: Dong
authors.forename: Jing-Quan
authors.initials: JQ
authors.lastname: He
authors.forename: Zhen
authors.initials: Z
authors.lastname: Chai
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001930:Brain Injuries / Q000209:etiology / Q000473:pathology*; D002545:Brain Ischemia / Q000150:complications; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D002614:Chelating Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D005260:Female; D005947:Glucose / Q000172:deficiency; D006624:Hippocampus / Q000473:pathology*; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000172:deficiency; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002614:Chelating Agents; D018683:Excitatory Amino Acid Agents; D053496:Inositol 1,4,5-Trisphosphate Receptors; C580990:Ip3r2 protein, mouse; D004533:Egtazic Acid; D005947:Glucose; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium
keywords: Astrocytic Ca(2+) wave; Extrasynaptic NMDA receptor; Gap junction; Ischemia