Investigating mechanisms underlying astrocytic involvement in depressive-like behavior and antidepressant action

Abstract

Major Depressive disorder (MDD) is a complex, multifactorial psychiatric illness which affects over 20% of the population worldwide. Despite its prevalence, our understanding of its pathophysiology is severely limited, thus hampering the development of novel therapeutic strategies. Currently prescribed antidepressant drugs are marred by several limitations including low efficacy, delayed onset of action and frequent relapse. Studies have shown that clinically depressed patients have decreased glial density especially astrocytes in brain regions involved in the regulation of mood-related behaviors such as the Prefrontal cortex and hippocampus. Selective ablation of astrocytes has been shown to induce depressive-like behavior, suggesting a causal link between astrocyte degeneration and the behavioral symptoms of major depressive disorder. Given the central role that hippocampus plays in the pathophysiology of depression and in the action of antidepressant drugs, changes in hippocampal astrocyte density and physiology may have significant effects on behavioral symptoms of MDD.

There is some preclinical and clinical evidence to believe that degenerative structural changes in astrocytes may play a very important role in the manifestation of depressive-like behavior. Hence, manipulating astrocyte structure can provide the basis for new therapeutic targets. We studied the effects of chronic stress exposure and different antidepressants administration on the hippocampal astrocytes. We observed that chronic stress exposure differentially affected astrocytes belonging to different subfields of hippocampus (Virmani et al., 2021). Among all the subfields, which include CA1, CA3, hilus and molecular layer, the molecular layer astrocytes showed significant decrease in the ramification with exposure to chronic stress. Interestingly, chronic administration of antidepressants increased the ramifications of the astrocytes. Different classes of antidepressants including classical and fast acting antidepressants were able to induce structural plasticity in astrocytes. Further, depletion of norepinephrine caused degeneration of astrocytes. From our studies, RhoA-ROCK pathway seem to be regulating the morphological changes in the astrocytes. Transcriptomic analysis from the mouse hippocampus administered with chronic antidepressant treatment indicated that these structural changes might be protective. We observed downregulation of pro inflammatory genes and upregulation of neuroprotective factor. We investigated the behavioral relevance of these structural changes using SrfGFAP-ERcKO transgenic mice.

These findings highlight the involvement of astrocytes in depression and antidepressant action and provide new targets for further studies on designing new therapeutics for depression.