Abstract
Glial dysfunction is a major pathophysiological feature of mood disorders. While altered astrocyte (AS) and oligodendrocyte-lineage (OL) functions have been associated with depression, the crosstalk between these glial cell types has never been assessed in that context. AS are potent regulators of myelination, in part through gap junction (GJ) channels formed by the heterotypic coupling of AS-specific (Cx30 and Cx43) and OL-specific (Cx32 and Cx47) connexins. This study therefore aimed at addressing the integrity of AS/OL coupling in the anterior cingulate cortex (ACC) of depressed suicides. Using immunofluorescence and confocal imaging, we characterized the distribution of Cx30 and mapped its expression onto OL somas, myelinated axons, and brain vasculature in postmortem brain samples from depressed suicides (N = 48) and matched controls (N = 23). Differential gene expression of key components of the GJ nexus was also screened through RNA-sequencing previously generated by our group, and validated by quantitative real-time PCR. We show that Cx30 expression localized onto OL cells and myelinated fibers is decreased in deep cortical layers of the ACC in male-depressed suicides. This effect was associated with decreased expression of OL-specific connexins, as well as the downregulation of major connexin-interacting proteins essential for the scaffolding, trafficking, and function of GJs. These results provide a first evidence of impaired AS/OL GJ-mediated communication in the ACC of individuals with mood disorders. These changes in glial coupling are likely to have significant impact on brain function, and may contribute to the altered OL function previously reported in this brain region.
Highlights
Glial dysfunction is a pathophysiological hallmark of depression
In this study, we asked whether AS/OL communication could be impaired in depressed suicides, as previous evidence had linked changes in the expression of astrocytic connexins as well as myelin and OL function impairments in this population
We characterized the distribution of connexin 30 (Cx30) in the human postmortem anterior cingulate cortex (ACC), and found that Cx30 immunoreactivity is selectively decreased around somas of mature OLs and along myelinated fibers in depressed suicides, suggesting that AS/OL Cx30mediated coupling may be disrupted
Summary
Glial dysfunction is a pathophysiological hallmark of depression. Postmortem studies have consistently shown changes in astrocyte (AS) numbers and morphology, as well as in the expression of astrocytic markers in fronto-limbic regions of depressed individuals [1,2,3,4,5,6,7,8,9,10], while pharmacological or genetic disruption of AS function in rodents has been associated with depressive-like behavior [11, 12]. Oligodendrocyte-lineage (OL) cells, which allow for a formidable form of brain plasticity by responding to environmental cues and experiences in an activitydependent manner [13,14,15], were found to display functional impairments in both postmortem brain samples from depressed individuals [16,17,18,19,20,21,22,23,24] and animal models mimicking some aspects of depression following stress exposure [25,26,27] This could represent a neurobiological substrate to the altered connectivity and white matter integrity that have been reported in imaging studies [28,29,30,31,32,33,34,35], highlighting that myelin plasticity in discrete corticolimbic areas could mediate some of the behavioral changes characterizing depression or modulate individual vulnerability to this mood disorder. Functional channels are formed between ASs and OLs through the heterotypic coupling of Cx30–Cx32 and Cx43–Cx47 [41, 43,44,45,46,47], and this glial GJ coupling is critical for OL function, including normal myelination [48,49,50,51]
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