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We elucidated how GLAST was regulated in rat chronic ocular hypertension (COH) model. Western blot and whole\u2010cell patch\u2010clamp recordings showed that GLAST proteins and GLAST\u2010mediated current densities in M\u00fcller cells were downregulated at the early stages of COH. In normal rats, intravitreal injection of the ephrinA3 activator EphA4\u2010Fc mimicked the changes of GLAST in COH retinas. In purified cultured M\u00fcller cells, EphA4\u2010Fc treatment reduced GLAST expression at mRNA and protein levels, which was reversed by the tyrosine kinase inhibitor PP2 or transfection with ephrinA3\u2010siRNA (Si\u2010EFNA3), suggesting that EphA4\/ephrinA3 reverse signaling mediated GLAST downregulation. EphA4\/ephrinA3 reverse signaling\u2010induced GLAST downregulation was mediated by inhibiting PI3K\/Akt\/NF\u2010\u03baB pathways since EphA4\u2010Fc treatment of cultured M\u00fcller cells reduced the levels of p\u2010Akt\/Akt and NF\u2010\u03baB p65, which were reversed by transfecting Si\u2010EFNA3. In M\u00fcller cells with ephrinA3 knockdown, the PI3K inhibitor LY294002 still decreased the protein levels of NF\u2010\u03baB p65 in the presence of EphA4\u2010Fc, and the mRNA levels of GLAST were reduced by LY294002 and the NF\u2010\u03baB inhibitor SN50, respectively. Pre\u2010injection of the PI3K\/Akt pathway activator 740 Y\u2010P reversed the GLAST downregulation in COH retinas. Western blot and TUNEL staining showed that transfecting of Si\u2010EFNA3 reduced M\u00fcller cell gliosis and RGC apoptosis in COH retinas. Our results suggest that activated EphA4\/ephrinA3 reverse signaling induces GLAST downregulation in M\u00fcller cells via inhibiting PI3K\/Akt\/NF\u2010\u03baB pathways, thus contributing to RGC damage in glaucoma.<\/jats:p>","DOI":"10.1002\/glia.24307","type":"journal-article","created":{"date-parts":[[2022,11,23]],"date-time":"2022-11-23T10:57:19Z","timestamp":1669201039000},"page":"720-741","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["<scp>EphA4<\/scp>\/<scp>ephrinA3<\/scp> reverse signaling mediated downregulation of glutamate transporter <scp>GLAST<\/scp> in M\u00fcller cells in an experimental glaucoma model"],"prefix":"10.1002","volume":"71","author":[{"given":"Zhi\u2010Xin","family":"Zhou","sequence":"first","affiliation":[{"name":"State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin\u2010Jie","family":"Xu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong\u2010Ning","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuo","family":"Cheng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3948-2943","authenticated-orcid":false,"given":"Yanying","family":"Miao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Lei","sequence":"additional","affiliation":[{"name":"Institutes of Neuroscience and Third Affiliated Hospital, Henan Provincial People's Hospital, Henan Eye Institute, Henan Eye Hospital, People's Hospital of Zhengzhou University Zhengzhou University  Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Gao","sequence":"additional","affiliation":[{"name":"Eye Institute and Department of Ophthalmology, Eye &amp; 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