Bidirectional regulation of glial potassium buffering: glioprotection versus neuroprotection

  1. Hailun Li
  2. Lorenzo Lones
  3. Aaron DiAntonio  Is a corresponding author
  1. Washington University School of Medicine, United States

Abstract

Glia modulate neuronal excitability and seizure sensitivity by maintaining potassium and water homeostasis. A SIK3-regulated gene expression program controls the glial capacity to buffer K+ and water in Drosophila, however upstream regulatory mechanisms are unknown. Here we identify an octopaminergic circuit linking neuronal activity to glial ion and water buffering. Under basal conditions, octopamine functions through the inhibitory octopaminergic GPCR OctbR to upregulate glial buffering capacity, while under pathological K+ stress, octopamine signals through the stimulatory octopaminergic GPCR OAMB1 to downregulate the glial buffering program. Failure to downregulate this program leads to intracellular glia swelling and stress signaling, suggesting that turning down this pathway is glioprotective. In the eag shaker Drosophila seizure model, the SIK3-mediated buffering pathway in inactivated. Re-activation of the glial buffering program dramatically suppresses neuronal hyperactivity, seizures, and shortened lifespan in this mutant. These findings highlight the therapeutic potential of a glial-centric therapeutic strategy for diseases of hyperexcitability.

Data availability

All data generated or analyzed during this study are included in the manuscript.

Article and author information

Author details

  1. Hailun Li

    Developmental Biology, Needleman Center for Neurometabolism and Axonal Therapeutics, Washington University School of Medicine, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Lorenzo Lones

    Developmental Biology, Needleman Center for Neurometabolism and Axonal Therapeutics, Washington University School of Medicine, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Aaron DiAntonio

    Developmental Biology, Needleman Center for Neurometabolism and Axonal Therapeutics, Washington University School of Medicine, St. Louis, United States
    For correspondence
    diantonio@wustl.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7262-0968

Funding

National Institutes of Health (NS065053)

  • Aaron DiAntonio

American Heart Association (18PRE34030101)

  • Hailun Li

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

Reviewing Editor

  1. Graeme W Davis, University of California, San Francisco, United States

Publication history

  1. Received: August 30, 2020
  2. Accepted: February 26, 2021
  3. Accepted Manuscript published: March 1, 2021 (version 1)
  4. Version of Record published: March 9, 2021 (version 2)

Copyright

© 2021, Li 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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  1. Hailun Li
  2. Lorenzo Lones
  3. Aaron DiAntonio
(2021)
Bidirectional regulation of glial potassium buffering: glioprotection versus neuroprotection
eLife 10:e62606.
https://doi.org/10.7554/eLife.62606
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