PT  - JOURNAL ARTICLE
AU  - Marc Duque
AU  - Alex B. Chen
AU  - Sujatha Narayan
AU  - David E. Olson
AU  - Mark C. Fishman
AU  - Florian Engert
AU  - Misha B. Ahrens
TI  - Astroglial mediation of fast-acting antidepressant effect in zebrafish
AID  - 10.1101/2022.12.29.522099
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.12.29.522099
4099  - http://biorxiv.org/content/early/2022/12/29/2022.12.29.522099.short
4100  - http://biorxiv.org/content/early/2022/12/29/2022.12.29.522099.full
AB  - 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 StatementDEO 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.