Mechanism and consequence of abnormal calcium homeostasis in Rett syndrome astrocytes

  1. Qiping Dong
  2. Qing Liu
  3. Ronghui Li
  4. Anxin Wang
  5. Qian Bu
  6. Kuan-Hong Wang
  7. Qiang Chang  Is a corresponding author
  1. University of Wisconsin-Madison, United States
  2. National Institute of Mental Health, United States

Abstract

Astrocytes play an important role in Rett syndrome (RTT) disease progression. Although the non-cell-autonomous effect of RTT astrocytes on neurons was documented, cell-autonomous phenotypes and mechanisms within RTT astrocytes are not well understood. We report that spontaneous calcium activity is abnormal in RTT astrocytes in vitro, in situ, and in vivo. Such abnormal calcium activity is mediated by calcium overload in the endoplasmic reticulum caused by abnormal store operated calcium entry, which is in part dependent on elevated expression of TRPC4. Furthermore, the abnormal calcium activity leads to excessive activation of extrasynaptic NMDA receptors (eNMDARs) on neighboring neurons and increased network excitability in Mecp2 knockout mice. Finally, both the abnormal astrocytic calcium activity and the excessive activation of eNMDARs are caused by Mecp2 deletion in astrocytes in vivo. Our findings provide evidence that abnormal calcium homeostasis is a key cell-autonomous phenotype in RTT astrocytes, and reveal its mechanism and consequence.

Article and author information

Author details

  1. Qiping Dong

    Waisman Center, University of Wisconsin-Madison, Madison, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Qing Liu

    Unit on Neural Circuits and Adaptive Behaviors, National Institute of Mental Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Ronghui Li

    Waisman Center, University of Wisconsin-Madison, Madison, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6329-5895
  4. Anxin Wang

    Waisman Center, University of Wisconsin-Madison, Madison, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Qian Bu

    Waisman Center, University of Wisconsin-Madison, Madison, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Kuan-Hong Wang

    Unit on Neural Circuits and Adaptive Behaviors, National Institute of Mental Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Qiang Chang

    Waisman Center, University of Wisconsin-Madison, Madison, United States
    For correspondence
    qchang@waisman.wisc.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7625-2170

Funding

National Institute of Neurological Disorders and Stroke (R21NS081484)

  • Qiang Chang

National Institute of Mental Health (ZIAMH002897)

  • Kuan-Hong Wang

Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD090256)

  • Qiang Chang

Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD064743)

  • Qiang Chang

National Institute of Neurological Disorders and Stroke (R56NS100024)

  • Qiang Chang

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 (G005315) of the University of Wisconsin-Madison

Reviewing Editor

  1. Beth Stevens, Boston Children's Hospital, Harvard Medical School, United States

Publication history

  1. Received: November 7, 2017
  2. Accepted: March 28, 2018
  3. Accepted Manuscript published: March 29, 2018 (version 1)
  4. Version of Record published: April 16, 2018 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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  1. Qiping Dong
  2. Qing Liu
  3. Ronghui Li
  4. Anxin Wang
  5. Qian Bu
  6. Kuan-Hong Wang
  7. Qiang Chang
(2018)
Mechanism and consequence of abnormal calcium homeostasis in Rett syndrome astrocytes
eLife 7:e33417.
https://doi.org/10.7554/eLife.33417

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