Major depressive disorder (MDD) is one of the most common neuropsychiatric disorders affecting over one-fifth of the population worldwide. Owing to our limited understanding of the pathophysiology of MDD, the quest for finding novel antidepressant drug targets is severely impeded. Monoamine hypothesis of MDD provides a robust theoretical framework, forming the core of a large jigsaw puzzle, around which we must look for the vital missing pieces. Growing evidence suggests that the glial loss observed in key regions of the limbic system in depressed patients, at least partly, accounts for the structural and cognitive manifestations of MDD. Studies in animal models have subsequently hinted at the possibility that the glial atrophy may play a causative role in the precipitation of depressive symptoms. Antidepressants as well as monoamine neurotransmitters exert profound effects on the gene expression and metabolism in astrocytes. This raises an intriguing possibility that the astrocytes may play a central role alongside neurons in the behavioral effects of antidepressant drugs. In this article, we discuss the gene expression and metabolic changes brought about by antidepressants in astrocytes, which could be of relevance to synaptic plasticity and behavioral effects of antidepressant treatments.
Major depressive disorder (MDD) is a debilitating neuropsychiatric illness affecting 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. Recent advances have clearly established astrocytes as major players in the pathophysiology, and plausibly pathogenesis, of major depression. In particular, astrocyte density in the hippocampus is severely diminished in MDD patients and correlates strongly with the disease outcome. Moreover, astrocyte densities from different subfields of the hippocampus show varying trends in terms of their correlation to the disease outcome. 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 a significant effect on behavioral symptoms of MDD. In this study, we used chronic mild unpredictable stress (CMUS) in mice, which induces a depressive-like state, and examined its effects on astrocytes from different subfields of the hippocampus. We used SOX9 and S100β immunostaining to estimate the number of astrocytes per square millimeter from various hippocampal subfields. Furthermore, using confocal images of fluorescently labeled glial fibrillary acidic protein (GFAP)-immunopositive hippocampal astrocytes, we quantified various morphology-related parameters and performed Sholl analysis. We found that CMUS exerts differential effects on astrocyte cell numbers, ramification, cell radius, surface area, and process width of hippocampal astrocytes from different hippocampal subfields. Taken together, our study reveals that chronic stress does not uniformly affect all hippocampal astrocytes; but exerts its effects differentially on different astrocytic subpopulations within the hippocampus.
Major Depressive Disorder (MDD) is a debilitating neuropsychiatric illness affecting 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. Recent advances have clearly established astrocytes as major players in the pathophysiology, and plausibly pathogenesis, of major depression. In particular, astrocyte density in the hippocampus is severely diminished in MDD patients and correlates strongly with the disease outcome. Moreover, astrocyte densities from different subfields of the hippocampus show varying trends in terms of their correlation to the disease outcome. 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 a significant effect on behavioral symptoms of MDD. In this study, we used Chronic Mild Unpredictable Stress (CMUS) in mice, which induces a depressive-like state, and examined its effects on astrocytes from different subfields of the hippocampus. We used S100β immunostaining to estimate the number of astrocytes per mm 2 from various hippocampal subfields. Furthermore, using confocal images of fluorescently labeled GFAPimmunopositive hippocampal astrocytes, we quantified various morphology-related parameters and performed Sholl analysis. We found that CMUS exerts differential effects on astrocyte cell density, ramification, cell radius, surface area, and process width of hippocampal astrocytes from different hippocampal subfields. Taken together, our study reveals that chronic stress doesn't uniformly affect all hippocampal astrocytes; but exerts its effects differentially on different astrocytic subpopulations within the hippocampus.
Authors would like to thank Mr M. Manjunath and the staff at the central animal facility at IISc for technical help.
Nervous system development and plasticity involve changes in cellular morphology, making morphological analysis a valuable exercise in the study of nervous system development, function and disease. Morphological analysis is a time-consuming exercise requiring meticulous manual tracing of cellular contours and extensions. We have developed a software tool, called SMorph, to rapidly analyze the morphology of cells of the nervous system. SMorph performs completely automated Sholl analysis. It extracts 23 morphometric features based on cell images and Sholl analysis parameters, followed by principal component analysis (PCA). SMorph was tested on neurons, astrocytes and microglia and reveals subtle changes in cell morphology. Using SMorph, we found that chronic 21-day treatment with the antidepressant desipramine results in a significant structural remodeling in hippocampal astrocytes in mice. Given the proposed involvement of astroglial structural changes and atrophy in major depression in humans, our results reveal a novel kind of structural plasticity induced by chronic antidepressant administration.
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