The Study of Oligodendrocyte Pathology Using Postmortem Tissue From Brain Donors Reveals Unique Targets for the Development of Novel Antidepressants

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Oligodendrocytes are predominately found in white matter of the brain, but also populate gray matter regions. Although commonly known to provide myelination of neuronal axons, these cells serve numerous other functions in the brain. A unique property of oligodendrocytes is their inherent susceptibility to oxidative stress because of several biochemical characteristics of these cells, including a high concentration of iron, high metabolic rate, and low antioxidant enzyme activity. Oxidative stress conditions are produced by inflammation, and both inflammation and oxidative stress are highly associated with major depressive disorder (MDD). Hence, the study of oligodendrocytes in the brain in MDD readily provides access to molecular mechanisms engaged by oxidative stress conditions that putatively contribute to the etiology of MDD. My laboratory studied oligodendrocytes, and other white matter cells, from postmortem tissue collected from brain donors that died as a result of suicide and other causes, focusing on those donors who had at the time of death either MDD or no psychiatric or neurologic diagnosis (controls). White matter oligodendrocytes or whole white matter in limbic brain from MDD/suicide donors demonstrated indices of elevated oxidative damage, including increased DNA oxidation, shortened telomere DNA, reduced expression of antioxidant enzyme genes, and upregulated DNA base excision repair enzymes. These abnormalities were either not observed or were only modestly evident in astrocytes collected from white matter of the same MDD/suicide donors. To determine whether this oxidative damage was restricted to white matter in the limbic brain, oligodendrocytes were captured from three other brain regions, prefrontal cortical (BA 10) white matter, occipital cortical white matter, and gray matter in the region of the brainstem locus coeruleus. Shortened telomeres and reduced expression of antioxidant enzyme genes were observed in oligodendrocytes from these additional brain regions in MDD/suicide. Since this oligodendrocyte pathology was not anatomically restricted to the limbic brain, it may be difficult to understand how it is relevant to the biological basis of emotional behaviors that are specifically associated with MDD or suicide. However, the oligodendrocyte is highly susceptible to oxidative stress; hence, the oligodendrocyte can be viewed as a “canary in the coal mine” for detecting oxidative damage to the brain. Therefore, elucidation of the molecular pathways activated by oxidative damage in these cells could reveal novel targets for the development of drugs to prevent oxidative damage and its subsequent pathological activation of downstream pathways deleterious to brain cell health. As such, drugs targeting these pathways may have antidepressant properties in humans, and could provide an alternative approach to treating depression and reducing suicide risk. In fact, we found that repeated exposure of rats to psychological stress increased DNA oxidation in prefrontal cortical white matter. Furthermore, preliminary findings using rat models of depression reveal that interruption of pathways downstream to oxidative damage produces a robust antidepressant response, correcting depressive-like behaviors elicited by psychological stress. These findings strongly implicate a role of oxidative damage in the etiology of MDD and possibly suicide, and demonstrate the utility of studying brain pathology as a logical path to identifying novel antidepressant targets.


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