From metabolism to mood regulation: astrocytes as a driver of depression

Astrocytes are increasingly recognized as active regulators of mood and cognition, extending far beyond their classical supportive roles. In major depressive disorder, converging evidence from postmortem analyses, magnetic resonance spectroscopy (MRS), and animal stress models points toward the possibility of astrocytic abnormalities, including reduced density, impaired glutamate-glutamine cycling, and altered mitochondrial function. However, the causal contribution of these alterations remains insufficiently defined. This review aims to summarize experimental studies employing both loss- and gain-of-function approaches to directly probe the involvement of astrocytes in depression. We first introduce which inhibited astrocytic functions induce depressive-like behaviors, and then explore how enhancing these astrocytic functions-through overexpression and pharmacological manipulation methods-rescues stress-induced depression phenotypes. We further connect astrocyte alterations with circuit-level dysfunctions and behavioral outcomes, such as impaired prefrontal-amygdala regulation and reduced mesolimbic reward responses. Finally, we discuss therapeutic opportunities including astrocyte-targeting pharmacological strategies and MRS-based biomarkers. By integrating mechanistic evidence with translational perspectives, this review positions astrocyte metabolism as a promising frontier for antidepressant development.