Mechanism and consequence of abnormal calcium homeostasis in Rett syndrome astrocytes
- University of Wisconsin-Madison, United States
- 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.
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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
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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Mechanism and consequence of abnormal calcium homeostasis in Rett syndrome astrocytes
eLife 7:e33417.
https://doi.org/10.7554/eLife.33417
