1. Neuroscience
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Sonic hedgehog signaling in astrocytes mediates cell-type-specific synaptic organization

  1. Steven A Hill
  2. Andrew S Blaeser
  3. Austin A Coley
  4. Yajun Xie
  5. Katherine A Shepard
  6. Corey C Harwell
  7. Wen-Jun Gao
  8. A Denise R Garcia  Is a corresponding author
  1. Drexel University, United States
  2. Drexel University College of Medicine, United States
  3. Harvard Medical School, United States
Research Article
  • Cited 5
  • Views 2,486
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Cite this article as: eLife 2019;8:e45545 doi: 10.7554/eLife.45545

Abstract

Astrocytes have emerged as integral partners with neurons in regulating synapse formation and function, but the mechanisms that mediate these interactions are not well understood. Here, we show that Sonic hedgehog (Shh) signaling in mature astrocytes is required for establishing structural organization and remodeling of cortical synapses in a cell type-specific manner. In the postnatal cortex, Shh signaling is active in a subpopulation of mature astrocytes localized primarily in deep cortical layers. Selective disruption of Shh signaling in astrocytes produces a dramatic increase in synapse number specifically on layer V apical dendrites that emerges during adolescence and persists into adulthood. Dynamic turnover of dendritic spines is impaired in mutant mice and is accompanied by an increase in neuronal excitability and a reduction of the glial-specific, inward-rectifying K+ channel Kir4.1. These data identify a critical role for Shh signaling in astrocyte-mediated modulation of neuronal activity required for sculpting synapses.

Article and author information

Author details

  1. Steven A Hill

    Department of Biology, Drexel University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Andrew S Blaeser

    Department of Biology, Drexel University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Austin A Coley

    Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Yajun Xie

    Department of Neurobiology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Katherine A Shepard

    Department of Biology, Drexel University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Corey C Harwell

    Department of Neurobiology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Wen-Jun Gao

    Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. A Denise R Garcia

    Department of Biology, Drexel University, Philadelphia, United States
    For correspondence
    adg82@drexel.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5809-3543

Funding

National Institute of Neurological Disorders and Stroke (1R01NS096100)

  • A Denise R Garcia

Louis Perry Jones (Postdoctoral Fellowship)

  • Yajun Xie

National Institute of Mental Health (7K01MH097957)

  • A Denise R Garcia

National Institute of Mental Health (5R21MH110724)

  • A Denise R Garcia

PA Department of Health, CURE

  • Wen-Jun Gao
  • A Denise R Garcia

National Institute of Neurological Disorders and Stroke (F99NS105185)

  • Austin A Coley

National Institute of Mental Health (R01MH085666)

  • Wen-Jun Gao

National Institute of Neurological Disorders and Stroke (K01NS089720)

  • Corey C Harwell

National Institute of Neurological Disorders and Stroke (R01NS102228)

  • Corey C Harwell

Genise Goldenson (Junior Faculty Award)

  • Corey C Harwell

Alice and Joseph Brooks Fund (Postdoctoral Fellowship)

  • Yajun Xie

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#20476) of Drexel University. All surgery was performed under isoflurane or ketamine/xylazine anesthesia, and every effort was made to minimize suffering.

Reviewing Editor

  1. Dwight E Bergles, Johns Hopkins University School of Medicine, United States

Publication history

  1. Received: January 26, 2019
  2. Accepted: June 13, 2019
  3. Accepted Manuscript published: June 13, 2019 (version 1)
  4. Version of Record published: July 15, 2019 (version 2)

Copyright

© 2019, Hill et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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