Astroglia and depression: A Gliocentric perspective from rodent models to therapeutic insights

Major depressive disorder (MDD) is a debilitating neuropsychiatric condition that affects individuals worldwide. While neuronal deficits have long been recognized in depression pathogenesis, astroglia are increasingly gaining attention. Astroglia are essential for maintaining brain homeostasis, and regulate neurotransmission, neuroinflammation, and metabolic processes that are disrupted in MDD. This review synthesizes findings from current rodent models of depression, which, despite variations in protocols and etiologies, reveal consistent disruptions related to astroglial function. Structural astroglial abnormalities, including atrophy in the prefrontal cortex and hippocampus along with a reduction in the number of cells expressing the astroglial marker, glial fibrillary acidic protein, are commonly observed. Additional intracellular and intercellular disturbances include impaired glutamate homeostasis, reduced neurotrophic factor production, disrupted gap junction communication with decreased connexin 43 expression, diminished lactate release, increased neuroinflammation, and synaptic deficits. Clinical studies corroborate these findings through postmortem brain analyses and serum biomarkers revealing astroglial dysfunction in the cortical regions of patients with MDD. Importantly, standard and atypical antidepressants, including selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, and serotonin modulators, as well as rapid-acting antidepressants such as ketamine and esketamine, exert their therapeutic effects at least partially by restoring astroglial homeostasis, highlighting astroglia as critical mediators of treatment response. These converging lines of evidence position astroglial dysfunction as a fundamental component of the pathophysiology of depression and a promising target for effective, personalized antidepressant strategies that move beyond exclusively neuron-centric approaches.