title: Astrocyte response to motor neuron injury promotes structural synaptic plasticity via STAT3-regulated TSP-1 expression.
abstract: The role of remote astrocyte (AC) reaction to central or peripheral axonal insult is not clearly understood. Here we use a transgenic approach to compare the direct influence of normal with diminished AC reactivity on neuronal integrity and synapse recovery following extracranial facial nerve transection in mice. Our model allows straightforward interpretations of AC-neuron signalling by reducing confounding effects imposed by inflammatory cells. We show direct evidence that perineuronal reactive ACs play a major role in maintaining neuronal circuitry following distant axotomy. We reveal a novel function of astrocytic signal transducer and activator of transcription-3 (STAT3). STAT3 regulates perineuronal astrocytic process formation and re-expression of a synaptogenic molecule, thrombospondin-1 (TSP-1), apart from supporting neuronal integrity. We demonstrate that, through this new pathway, TSP-1 is responsible for the remote AC-mediated recovery of excitatory synapses onto axotomized motor neurons in adult mice. These data provide new targets for neuroprotective therapies via optimizing AC-driven plasticity.
authors.affiliation: John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, E.D. Adrian Building, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK.
authors.forename: Giulia E
authors.initials: GE
authors.lastname: Tyzack
authors.affiliation: 1] Department of Veterinary Medicine & Wellcome Trust-MRC Stem Cell Institute, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK [2].
authors.forename: Sergey
authors.initials: S
authors.lastname: Sitnikov
authors.affiliation: 1] John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, E.D. Adrian Building, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK [2].
authors.forename: Daniel
authors.initials: D
authors.lastname: Barson
authors.affiliation: John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, E.D. Adrian Building, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK.
authors.forename: Kerala L
authors.initials: KL
authors.lastname: Adams-Carr
authors.affiliation: John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, E.D. Adrian Building, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK.
authors.forename: Nike K
authors.initials: NK
authors.lastname: Lau
authors.affiliation: John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, E.D. Adrian Building, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK.
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Kwok
authors.affiliation: 1] John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, E.D. Adrian Building, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK [2] Department of Veterinary Medicine & Wellcome Trust-MRC Stem Cell Institute, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhao
authors.affiliation: 1] John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, E.D. Adrian Building, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK [2] Department of Veterinary Medicine & Wellcome Trust-MRC Stem Cell Institute, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK.
authors.forename: Robin J M
authors.initials: RJ
authors.lastname: Franklin
authors.affiliation: 1] John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, E.D. Adrian Building, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK [2] Department of Veterinary Medicine & Wellcome Trust-MRC Stem Cell Institute, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK.
authors.forename: Ragnhildur T
authors.initials: RT
authors.lastname: Karadottir
authors.affiliation: John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, E.D. Adrian Building, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK.
authors.forename: James W
authors.initials: JW
authors.lastname: Fawcett
authors.affiliation: John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, E.D. Adrian Building, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK.
authors.forename: András
authors.initials: A
authors.lastname: Lakatos
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000502:physiology*; D019771:Axotomy; D002478:Cells, Cultured; D020220:Facial Nerve Injuries / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D023421:Models, Animal; D009046:Motor Neurons / Q000502:physiology*; D009416:Nerve Regeneration / Q000502:physiology; D009473:Neuronal Plasticity / Q000502:physiology*; D018408:Patch-Clamp Techniques; D050796:STAT3 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013569:Synapses / Q000502:physiology*; D019700:Thrombospondin 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D019700:Thrombospondin 1; C585483:Thbs1 protein, mouse