Astrocyte response to motor neuron injury promotes structural synaptic plasticity via STAT3-regulated TSP-1 expression

Giulia E. Tyzack; Sergey Sitnikov; Daniel Barson; Kerala L. Adams-Carr; Nike K. Lau; Jessica C. Kwok; Chao Zhao; Robin J.M. Franklin; Ragnhildur T. Karadottir; James W. Fawcett; András Lakatos

doi:10.1038/ncomms5294

Astrocyte response to motor neuron injury promotes structural synaptic plasticity via STAT3-regulated TSP-1 expression

Giulia E. Tyzack, Sergey Sitnikov, Daniel Barson, Kerala L. Adams-Carr, Nike K. Lau, Jessica C. Kwok, Chao Zhao, Robin J.M. Franklin, Ragnhildur T. Karadottir, James W. Fawcett, András Lakatos^*

^*Corresponding author for this work

Faculty of Medicine

Research output: Contribution to journal › Article › peer-review

89 Citations (Scopus)

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.

Original language	English
Article number	4294
Journal	Nature Communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms5294
Publication status	Published - 11 Jul 2014

Bibliographical note

Funding Information:
This work has been mainly supported by the Walker Fellowship (A.L.) at the University of Cambridge and by the Van Geest Fund (G.E.T.). We also received personal support by the Gates Scholarship (D.B., S.S.) and the Wellcome Trust Biomedical Vacation Scholarship (N.K.L., A.L.; RG60754). The authors are also grateful to Dr A. Tolkovsky for reading the manuscript and for her useful comments. We are grateful to Professor M. Sofroniew (UCLA, USA) for his advice and providing the STAT3-GFAP-CKO mice and to Professor G. Raivich for commenting on our work. We thank Dr C. Eroglu for the availability of the puncta analyzer software for synapse analysis (developed by B. Wark in Professor B. Barres’ laboratory) and to Dr J. Skepper for the help with electron microscopy.

Access to Document

10.1038/ncomms5294

Cite this

@article{44fcbf7f399b408f9000fe56c2f7e820,

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.",

author = "Tyzack, {Giulia E.} and Sergey Sitnikov and Daniel Barson and Adams-Carr, {Kerala L.} and Lau, {Nike K.} and Kwok, {Jessica C.} and Chao Zhao and Franklin, {Robin J.M.} and Karadottir, {Ragnhildur T.} and Fawcett, {James W.} and Andr{\'a}s Lakatos",

note = "Funding Information: This work has been mainly supported by the Walker Fellowship (A.L.) at the University of Cambridge and by the Van Geest Fund (G.E.T.). We also received personal support by the Gates Scholarship (D.B., S.S.) and the Wellcome Trust Biomedical Vacation Scholarship (N.K.L., A.L.; RG60754). The authors are also grateful to Dr A. Tolkovsky for reading the manuscript and for her useful comments. We are grateful to Professor M. Sofroniew (UCLA, USA) for his advice and providing the STAT3-GFAP-CKO mice and to Professor G. Raivich for commenting on our work. We thank Dr C. Eroglu for the availability of the puncta analyzer software for synapse analysis (developed by B. Wark in Professor B. Barres{\textquoteright} laboratory) and to Dr J. Skepper for the help with electron microscopy.",

year = "2014",

month = jul,

day = "11",

doi = "10.1038/ncomms5294",

language = "English",

volume = "5",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Astrocyte response to motor neuron injury promotes structural synaptic plasticity via STAT3-regulated TSP-1 expression

AU - Tyzack, Giulia E.

AU - Sitnikov, Sergey

AU - Barson, Daniel

AU - Adams-Carr, Kerala L.

AU - Lau, Nike K.

AU - Kwok, Jessica C.

AU - Zhao, Chao

AU - Franklin, Robin J.M.

AU - Karadottir, Ragnhildur T.

AU - Fawcett, James W.

AU - Lakatos, András

N1 - Funding Information: This work has been mainly supported by the Walker Fellowship (A.L.) at the University of Cambridge and by the Van Geest Fund (G.E.T.). We also received personal support by the Gates Scholarship (D.B., S.S.) and the Wellcome Trust Biomedical Vacation Scholarship (N.K.L., A.L.; RG60754). The authors are also grateful to Dr A. Tolkovsky for reading the manuscript and for her useful comments. We are grateful to Professor M. Sofroniew (UCLA, USA) for his advice and providing the STAT3-GFAP-CKO mice and to Professor G. Raivich for commenting on our work. We thank Dr C. Eroglu for the availability of the puncta analyzer software for synapse analysis (developed by B. Wark in Professor B. Barres’ laboratory) and to Dr J. Skepper for the help with electron microscopy.

PY - 2014/7/11

Y1 - 2014/7/11

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84904369793&partnerID=8YFLogxK

U2 - 10.1038/ncomms5294

DO - 10.1038/ncomms5294

M3 - Article

C2 - 25014177

AN - SCOPUS:84904369793

SN - 2041-1723

VL - 5

JO - Nature Communications

JF - Nature Communications

M1 - 4294

ER -

Astrocyte response to motor neuron injury promotes structural synaptic plasticity via STAT3-regulated TSP-1 expression

Abstract

Bibliographical note

Access to Document

Fingerprint

Cite this