Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Astroglial mediation of fast-acting antidepressant effect in zebrafish

View ORCID ProfileMarc Duque, View ORCID ProfileAlex B. Chen, View ORCID ProfileSujatha Narayan, View ORCID ProfileDavid E. Olson, Mark C. Fishman, Florian Engert, View ORCID ProfileMisha B. Ahrens
doi: https://doi.org/10.1101/2022.12.29.522099
Marc Duque
1Department of Molecular and Cellular Biology, Harvard University; Cambridge, MA 02138, USA
2Graduate Program in Neuroscience, Harvard Medical School; Boston, MA 02115, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Marc Duque
  • For correspondence: mduqueramirez@g.harvard.edu abchen@g.harvard.edu
Alex B. Chen
1Department of Molecular and Cellular Biology, Harvard University; Cambridge, MA 02138, USA
2Graduate Program in Neuroscience, Harvard Medical School; Boston, MA 02115, USA
3Janelia Research Campus, Howard Hughes Medical Institute; Ashburn, VA 20147, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Alex B. Chen
  • For correspondence: mduqueramirez@g.harvard.edu abchen@g.harvard.edu
Sujatha Narayan
3Janelia Research Campus, Howard Hughes Medical Institute; Ashburn, VA 20147, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Sujatha Narayan
David E. Olson
4Department of Chemistry, University of California, Davis; Davis, CA 95616, USA
5Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis; Sacramento, CA 95817, USA
6Center for Neuroscience, University of California, Davis; Davis, CA 95618, USA
7Institute for Psychedelics and Neurotherapeutics, University of California, Davis, Davis, CA 95616, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for David E. Olson
Mark C. Fishman
8Department of Stem Cell and Regenerative Biology, Harvard University; Cambridge, MA 02138, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Florian Engert
1Department of Molecular and Cellular Biology, Harvard University; Cambridge, MA 02138, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Misha B. Ahrens
3Janelia Research Campus, Howard Hughes Medical Institute; Ashburn, VA 20147, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Misha B. Ahrens
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

Abstract

Rapid-acting antidepressants like ketamine hold promise to change the approach to treatment of major depressive disorder (MDD),1–3 but their cellular and molecular targets remain unclear. Passivity induced by behavioral futility underlies learned helplessness, a process that becomes maladaptive in MDD.4, 5 Antidepressants inhibit futility-induced passivity (FIP) in rodent models such as the forced swimming6 or tail suspension7 tasks, but these models lack the throughput and accessibility for screening compounds and investigating their effects on the brain in vivo. Therefore, we adapted a recently discovered FIP behavior8 in the small and optically accessible larval zebrafish to create a scalable behavioral assay for antidepressant action. We found that rapid-acting antidepressants with diverse pharmacological targets demonstrated a suppression of FIP conserved between fish and rodents. While fast-acting antidepressants are thought to primarily target neurons,2, 9, 10 using brain-wide imaging in vivo we found, surprisingly, that ketamine, but not psychedelics or typical antidepressants, drove cytosolic calcium elevation in astroglia lasting many minutes. Blocking neural activity did not prevent ketamine’s effects on FIP or astroglial calcium, suggesting an astroglia-autonomous mechanism of ketamine’s action. Chemogenetic and optogenetic perturbations of astroglia reveal that the aftereffects of calcium elevation are sufficient to suppress FIP by inhibiting astroglial integration of futile swimming. In sum, our work provides evidence that ketamine exerts its antidepressant effects by inhibiting an astroglial population that integrates futility and changes behavioral state. Astroglia play central roles in modulating circuit dynamics,11 and our work argues that targeting astroglial signaling may be a fruitful strategy for designing new rapid-acting antidepressants.

Competing Interest Statement

DEO is a co-founder of Delix Therapeutics, Inc., serves as the Chief Innovation Officer and Head of the Scientific Advisory Board, and has sponsored research agreements with Delix Therapeutics. Delix Therapeutics has licensed technology from the University of California, Davis. All other authors declare that they have no competing interests.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
Back to top
PreviousNext
Posted December 29, 2022.
Download PDF

Supplementary Material

Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Astroglial mediation of fast-acting antidepressant effect in zebrafish
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Astroglial mediation of fast-acting antidepressant effect in zebrafish
Marc Duque, Alex B. Chen, Sujatha Narayan, David E. Olson, Mark C. Fishman, Florian Engert, Misha B. Ahrens
bioRxiv 2022.12.29.522099; doi: https://doi.org/10.1101/2022.12.29.522099
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
Astroglial mediation of fast-acting antidepressant effect in zebrafish
Marc Duque, Alex B. Chen, Sujatha Narayan, David E. Olson, Mark C. Fishman, Florian Engert, Misha B. Ahrens
bioRxiv 2022.12.29.522099; doi: https://doi.org/10.1101/2022.12.29.522099

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Neuroscience
Subject Areas
All Articles
  • Animal Behavior and Cognition (4116)
  • Biochemistry (8820)
  • Bioengineering (6523)
  • Bioinformatics (23469)
  • Biophysics (11798)
  • Cancer Biology (9216)
  • Cell Biology (13327)
  • Clinical Trials (138)
  • Developmental Biology (7440)
  • Ecology (11417)
  • Epidemiology (2066)
  • Evolutionary Biology (15160)
  • Genetics (10442)
  • Genomics (14050)
  • Immunology (9176)
  • Microbiology (22170)
  • Molecular Biology (8817)
  • Neuroscience (47600)
  • Paleontology (350)
  • Pathology (1429)
  • Pharmacology and Toxicology (2492)
  • Physiology (3733)
  • Plant Biology (8084)
  • Scientific Communication and Education (1437)
  • Synthetic Biology (2221)
  • Systems Biology (6039)
  • Zoology (1254)