title: Ephrin-A3 reverse signaling regulates hippocampal neuronal damage and astrocytic glutamate transport after transient global ischemia.
abstract: Increasing evidence indicates that the Eph receptors and their ephrin ligands are involved in the regulation of interactions between neurons and astrocytes. Moreover, astrocytic ephrin-A3 reverse signaling mediated by EphA4 receptors is necessary for controlling the abundance of glial glutamate transporters. However, the role of ephrin-A3 reverse signaling in astrocytic function and neuronal death under ischemic conditions remains unclear. In the present study, we found that the EphA4 receptor and its ephrin-A3 ligand, which were distributed in neurons and astrocytes, respectively, in the hippocampus showed a coincident up-regulation of protein expression in the early stage of ischemia. Application of clustered EphA4 decreased the expressions of astrocytic glutamate transporters together with astrocytic glutamate uptake capacity through activating ephrin-A3 reverse signaling. In consequence, neuronal loss was aggravated in the CA1 region of the hippocampus accompanied by impaired hippocampus-dependent spatial memory when clustered EphA4 treatment was administered prior to transient global ischemia. These findings indicate that EphA4-mediated ephrin-A3 reverse signaling is a crucial mechanism for astrocytes to control glial glutamate transporters and prevent glutamate excitotoxicity under pathological conditions. Astrocytic ephrin-A3 reverse signaling mediated by EphA4 receptor is necessary for controlling the abundance of glial glutamate transporters under physiological conditions. However, the role of ephrin-A3 reverse signaling in astrocytic function and neuronal death under ischemic conditions remains unclear. We found EphA4-mediated ephrin-A3 reverse signaling to be a crucial mechanism for astrocytes to control glial glutamate transporters and protect hippocampal neurons from glutamate excitotoxicity under ischemic conditions, this cascade representing a potential therapeutic target for stroke.
authors.affiliation: Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Jinshan
authors.initials: J
authors.lastname: Yang
authors.forename: Xiang
authors.initials: X
authors.lastname: Luo
authors.forename: Xiaojiang
authors.initials: X
authors.lastname: Huang
authors.forename: Qin
authors.initials: Q
authors.lastname: Ning
authors.forename: Minjie
authors.initials: M
authors.lastname: Xie
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D036384:Ephrin-A3 / Q000494:pharmacology*; D006624:Hippocampus / Q000473:pathology*; D007276:Injections, Intraventricular; D002546:Ischemic Attack, Transient / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009474:Neurons / Q000473:pathology*; D061251:Primary Cell Culture; D051381:Rats; D017207:Rats, Sprague-Dawley; D036081:Receptors, Eph Family / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D050496:Vesicular Glutamate Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D036384:Ephrin-A3; D050496:Vesicular Glutamate Transport Proteins; D036081:Receptors, Eph Family
keywords: glial ephrin-A3 reverse signaling; glial glutamate transporters; hippocampus; neuronal EphA4; transient global ischemia