Evidence of decreased gap junction coupling between astrocytes and oligodendrocytes in the anterior cingulate cortex of depressed suicides

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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.

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The subgenual anterior cingulate cortex in mood disorders.

Wayne C. Drevets, Jonathan Savitz, Michael Trimble (2008)

The anterior cingulate cortex (ACC) ventral to the genu of the corpus callosum has been implicated in the modulation of emotional behavior on the basis of neuroimaging studies in humans and lesion analyses in experimental animals. In a combined positron emission tomography/magnetic resonance imaging study of mood disorders, we demonstrated that the mean gray matter volume of this "subgenual" ACC (sgACC) cortex is abnormally reduced in subjects with major depressive disorder (MDD) and bipolar disorder, irrespective of mood state. Neuropathological assessments of sgACC tissue acquired postmortem from subjects with MDD or bipolar disorder confirmed the decrement in gray matter volume, and revealed that this abnormality was associated with a reduction in glia, with no equivalent loss of neurons. In positron emission tomography studies, the metabolic activity was elevated in this region in the depressed relative to the remitted phases of the same MDD subjects, and effective antidepressant treatment was associated with a reduction in sgACC activity. Other laboratories replicated and extended these findings, and the clinical importance of this treatment effect was underscored by a study showing that deep brain stimulation of the sgACC ameliorates depressive symptoms in treatment-resistant MDD. This article discusses the functional significance of these findings within the context of the preclinical literature that implicates the putative homologue of this region in the regulation of emotional behavior and stress response. In experimental animals, this region participates in an extended "visceromotor network" of structures that modulates autonomic/neuroendocrine responses and neurotransmitter transmission during the neural processing of reward, fear, and stress. These data thus hold important implications for the development of neural models of depression that can account for the abnormal motivational, neuroendocrine, autonomic, and emotional manifestations evident in human mood disorders.

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Glial loss in the prefrontal cortex is sufficient to induce depressive-like behaviors.

Mounira Banasr, Ronald S. Duman (2008)

Postmortem studies have repeatedly found decreased density and number of glia in cortical regions, including the prefrontal and cingulate areas, from depressed patients. However, it is unclear whether this glial loss plays a direct role in the expression of depressive symptoms. To address this question, we characterized the effects of pharmacologic glial ablation in the prefrontal cortex (PFC) of adult rats on behavioral tests known to be affected by stress or antidepressant treatments: sucrose preference test (SPT), novelty suppressed feeding test (NSFT), forced swim test (FST), and two-way active avoidance test (AAT). We established the dose and time course for the actions of an astrocyte specific toxin, L-alpha-aminoadipic acid (L-AAA), and compared the behavioral effects of this gliotoxin with the effects of an excitotoxic (ibotenate) lesion and to the effects of chronic stress. The results demonstrate that L-AAA infusions induced anhedonia in SPT, anxiety in NSFT, and helplessness in FST and AAT. These effects of L-AAA were similar to chronic unpredictable stress (CUS)-induced depressive-like behaviors in these tests. However, ibotenate-induced neurotoxic lesion of the PFC had no effect in these behavioral tests. The results demonstrate that glial ablation in the PFC is sufficient to induce depressive-like behaviors similar to chronic stress and support the hypothesis that loss of glia contributes to the core symptoms of depression.

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Anatomical Connectivity of the Subgenual Cingulate Region Targeted with Deep Brain Stimulation for Treatment-Resistant Depression

H. Johansen-Berg, D.A. Gutman, T.E.J. Behrens … (2007)

Chronic deep brain stimulation (DBS) of subgenual cingulate white matter results in dramatic remission of symptoms in some previously treatment-resistant depression patients. The effects of stimulation may be mediated locally or via corticocortical or corticosubcortical connections. We use tractography to define the likely connectivity of cingulate regions stimulated in DBS-responsive patients using diffusion imaging data acquired in healthy control subjects. We defined 2 distinct regions within anterior cingulate cortex based on anatomical connectivity: a pregenual region strongly connected to medial prefrontal and anterior midcingulate cortex and a subgenual region with strongest connections to nucleus accumbens, amygdala, hypothalamus, and orbitofrontal cortex. The location of electrode contact points from 9 patients successfully treated with DBS lies within this subgenual region. The anatomical connectivity of the subgenual cingulate region targeted with DBS for depression supports the hypothesis that treatment efficacy is mediated via effects on a distributed network of frontal, limbic, and visceromotor brain regions. At present, targeting of DBS for depression is based on landmarks visible in conventional magnetic resonance imaging. Preoperatively acquired diffusion imaging for connectivity-based cortical mapping could improve neurosurgical targeting. We hypothesize that the subgenual region with greatest connectivity across the distributed network described here may prove most effective.