Astroglial mediation of fast-acting antidepressant effect in zebrafish

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.