Sonic hedgehog signaling in astrocytes mediates cell-type-specific synaptic organization
- Drexel University, United States
- Drexel University College of Medicine, United States
- 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
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.
Reviewing Editor
- Dwight E Bergles, Johns Hopkins University School of Medicine, United States
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.
Version history
- Received: January 26, 2019
- Accepted: June 13, 2019
- Accepted Manuscript published: June 13, 2019 (version 1)
- 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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Sonic hedgehog signaling in astrocytes mediates cell-type-specific synaptic organization
eLife 8:e45545.
https://doi.org/10.7554/eLife.45545
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