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

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.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1-6.

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.

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.

Metrics

  • 5,281
    views
  • 679
    downloads
  • 67
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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
(2019)
Sonic hedgehog signaling in astrocytes mediates cell-type-specific synaptic organization
eLife 8:e45545.
https://doi.org/10.7554/eLife.45545

Share this article

https://doi.org/10.7554/eLife.45545

Further reading

    1. Neuroscience
    Sara A Nolin, Mary E Faulkner ... Kristina Visscher
    Research Article

    The brain is organized into systems and networks of interacting components. The functional connections among these components give insight into the brain's organization and may underlie some cognitive effects of aging. Examining the relationship between individual differences in brain organization and cognitive function in older adults who have reached oldest old ages with healthy cognition can help us understand how these networks support healthy cognitive aging. We investigated functional network segregation in 146 cognitively healthy participants aged 85+ in the McKnight Brain Aging Registry. We found that the segregation of the association system and the individual networks within the association system [the fronto-parietal network (FPN), cingulo-opercular network (CON) and default mode network (DMN)], has strong associations with overall cognition and processing speed. We also provide a healthy oldest-old (85+) cortical parcellation that can be used in future work in this age group. This study shows that network segregation of the oldest-old brain is closely linked to cognitive performance. This work adds to the growing body of knowledge about differentiation in the aged brain by demonstrating that cognitive ability is associated with differentiated functional networks in very old individuals representing successful cognitive aging.

    1. Neuroscience
    Olga Kepinska, Josue Dalboni da Rocha ... Narly Golestani
    Research Article

    This study examines whether auditory cortex anatomy reflects multilingual experience, specifically individuals’ phonological repertoire. Using data from over 200 participants exposed to 1–7 languages across 36 languages, we analyzed the role of language experience and typological distances between languages they spoke in shaping neural signatures of multilingualism. Our findings reveal a negative relationship between the thickness of the left and right second transverse temporal gyrus (TTG) and participants’ degree of multilingualism. Models incorporating phoneme-level information in the language experience index explained the most variance in TTG thickness, suggesting that a more extensive and more phonologically diverse language experience is associated with thinner cortices in the second TTG. This pattern, consistent across two datasets, supports the idea of experience-driven pruning and neural efficiency. Our findings indicate that experience with typologically distant languages appear to impact the brain differently than those with similar languages. Moreover, they suggest that early auditory regions seem to represent phoneme-level cross-linguistic information, contrary to the most established models of language processing in the brain, which suggest that phonological processing happens in more lateral posterior superior temporal gyrus (STG) and superior temporal sulcus (STS).