title: Astrocytic Ephrin-B1 Regulates Synapse Remodeling Following Traumatic Brain Injury.
abstract: Traumatic brain injury (TBI) can result in tissue alterations distant from the site of the initial injury, which can trigger pathological changes within hippocampal circuits and are thought to contribute to long-term cognitive and neuropsychological impairments. However, our understanding of secondary injury mechanisms is limited. Astrocytes play an important role in brain repair after injury and astrocyte-mediated mechanisms that are implicated in synapse development are likely important in injury-induced synapse remodeling. Our studies suggest a new role of ephrin-B1, which is known to regulate synapse development in neurons, in astrocyte-mediated synapse remodeling following TBI. Indeed, we observed a transient upregulation of ephrin-B1 immunoreactivity in hippocampal astrocytes following moderate controlled cortical impact model of TBI. The upregulation of ephrin-B1 levels in hippocampal astrocytes coincided with a decline in the number of vGlut1-positive glutamatergic input to CA1 neurons at 3 days post injury even in the absence of hippocampal neuron loss. In contrast, tamoxifen-induced ablation of ephrin-B1 from adult astrocytes in ephrin-B1(loxP/y)ERT2-Cre(GFAP) mice accelerated the recovery of vGlut1-positive glutamatergic input to CA1 neurons after TBI. Finally, our studies suggest that astrocytic ephrin-B1 may play an active role in injury-induced synapse remodeling through the activation of STAT3-mediated signaling in astrocytes. TBI-induced upregulation of STAT3 phosphorylation within the hippocampus was suppressed by astrocyte-specific ablation of ephrin-B1 in vivo, whereas the activation of ephrin-B1 in astrocytes triggered an increase in STAT3 phosphorylation in vitro. Thus, regulation of ephrin-B1 signaling in astrocytes may provide new therapeutic opportunities to aid functional recovery after TBI.
authors.affiliation: Biomedical Sciences Division, School of Medicine, University of California Riverside, CA, USA.
authors.forename: Angeliki M
authors.initials: AM
authors.lastname: Nikolakopoulou
authors.affiliation: Biomedical Sciences Division, School of Medicine, University of California Riverside, CA, USA Cell, Molecular, and Developmental Biology graduate program, University of California Riverside, CA, USA.
authors.forename: Jordan
authors.initials: J
authors.lastname: Koeppen
authors.affiliation: Biomedical Sciences Division, School of Medicine, University of California Riverside, CA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Garcia
authors.affiliation: Biomedical Sciences Division, School of Medicine, University of California Riverside, CA, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Leish
authors.affiliation: Department of Pediatrics, School of Medicine, Loma Linda University, CA, USA.
authors.forename: Andre
authors.initials: A
authors.lastname: Obenaus
authors.affiliation: Biomedical Sciences Division, School of Medicine, University of California Riverside, CA, USA Cell, Molecular, and Developmental Biology graduate program, University of California Riverside, CA, USA iryna.ethell@ucr.edu.
authors.forename: Iryna M
authors.initials: IM
authors.lastname: Ethell
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D000070642:Brain Injuries, Traumatic / Q000378:metabolism* / Q000473:pathology; D056547:CA1 Region, Hippocampal / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D036387:Ephrin-B1 / Q000235:genetics / Q000378:metabolism*; D005911:Gliosis / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism* / Q000473:pathology; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism
chemical_list: C092571:Efnb1 protein, mouse; D036387:Ephrin-B1; D050796:STAT3 Transcription Factor; C493465:Slc17a7 protein, mouse; C494087:Stat3 protein, mouse; D050598:Vesicular Glutamate Transport Protein 1
keywords: STAT3; astrocytes; ephrinB1; hippocampus; synapse; traumatic brain injury