Apoptosis-related proteins and proliferation markers in the orbitofrontal cortex in major depressive disorder

Abstract

Background: In major depressive disorder (MDD), lowered neural activity and significant reductions of markers of cell resiliency to degeneration occur in the prefrontal cortex (PFC). It is still unclear whether changes in other relevant markers of cell vulnerability to degeneration and markers of cell proliferation are associated with MDD. Methods: Levels of caspase 8 (C8), X-linked inhibitor of apoptosis protein (XIAP), direct IAP binding protein with low pI (DIABLO), proliferating cell nuclear antigen (PCNA) and density of cells immunoreactive (-IR) for proliferation marker Ki-67 were measured in postmortem samples of the left orbitofrontal cortex (OFC) of subjects with MDD, and psychiatrically-normal comparison subjects. Results: There was significant increase in C8, a higher ratio of DIABLO to XIAP, lower packing density of Ki-67-IR cells, and an unexpected age-dependent increase in PCNA in subjects with MDD vs. controls. PCNA levels were significantly higher in MDD subjects unresponsive to antidepressants or untreated with antidepressants. The DIABLO/XIAP ratio was higher in MDD subjects without antidepressants than in comparison subjects. Limitations: Qualitative nature of responsiveness assessments; Definition of resistance to antidepressant treatment is still controversial; Unclear role of PCNA. Conclusions: Markers of cell vulnerability to degeneration are increased and density of Ki67-positive cells is low MDD, but accompanied by normal XIAP levels. The results suggest increased vulnerability to cell pathology in depression that is insufficient to cause morphologically conspicuous cell death. Persistent but low-grade vulnerability to cell degeneration coexisting with reduced proliferation readiness may explain age-dependent reductions in neuronal densities in the OFC of depressed subjects.

Markers of Apoptosis Induction and Proliferation in the Orbitofrontal Cortex in Alcohol Dependence

“…However, these markers were significantly decreased in alcohol dependent subjects with comorbid major depression (Miguel-Hidalgo et al, 2010). In contrast, recently we found that there was a very significant decrease in the levels of connexin 43, the main gap junction forming protein in astrocytes, and in Cx43-immunoreactive gap junctions aggregates in alcohol dependent subjects regardless of the presence of depression (Miguel-Hidalgo et al, 2014). …”

“…We have recently found that in major depressive disorder (without comorbid alcoholism) there is an age-related increase in PCNA levels as compared to non-psychiatric control subjects (Miguel-Hidalgo et al, 2014) even if these subjects diagnosed with only depression had significantly lower density of Ki-67-immunoreactive cells. Thus, increased PCNA levels may signal not only direct alcohol effects on cellular function, but also altered neural activity patterns.…”

“…Five of the sample wells had proteins from subjects with major depression (but no alcohol dependence). The corresponding 5 blot lanes were dedicated to a separate study in which they were analyzed with the comparison subject lanes (Miguel-Hidalgo et al, 2014). These lanes are not included in any figures, results or statistics in the present article.…”

MicroRNA-21: Expression in oligodendrocytes and correlation with low myelin mRNAs in depression and alcoholism

“…The protocol included obtaining written consent from next-of-kin for retrospective interviews to compile relevant diagnostic information according to procedures detailed in previous publications (Miguel-Hidalgo et al, 2014; Whittom et al, 2014). Blocks of postmortem tissue were collected during autopsy at the Cuyahoga County Medical Examiner’s Office, Cleveland, Ohio.…”

The link between long noncoding RNAs and depression

“…Loss of hippocampal neurons is found in some depressed individuals and correlates with impaired memory and dysthymic mood (Sheline et al, 2003). Many other signaling pathways have also been reported to play important roles in the pathogenesis of MDD, such as hypothalamic-pituitary-adrenal (HPA)-axis, inflammatory pathways (Martin et al, 2015), the mammalian target of rapamycin (mTOR) signaling pathway (Jia and Le, 2015;Jernigan et al, 2011), and the extracellular signal-regulated kinase/ CREB/BDNF pathway (Wang et al, 2013), apoptosis (Miguel-Hidalgo et al, 2014), autophagy (Jia and Le, 2015;Gassen et al, 2015) and so on (for review, see (Chaudhury et al, 2015;Menard et al, 2015)). These evidences support the hypothesis that risk factors, which disrupt neuronal function and morphology resulting in dysfunction of the neural circuitry underlying the mood regulation and cognitive function through converging molecular and cellular mechanisms, may all contribute to the pathophysiology of MDD and are potential targets of antidepressants.…”