Widespread Decrease of Cerebral Vimentin-Immunoreactive Astrocytes in Depressed Suicides

Abstract

Post-mortem investigations have implicated cerebral astrocytes immunoreactive (-IR) for glial fibrillary acidic protein (GFAP) in the etiopathology of depression and suicide. However, it remains unclear whether astrocytic subpopulations IR for other astrocytic markers are similarly affected. Astrocytes IR to vimentin (VIM) display different regional densities than GFAP-IR astrocytes in the healthy brain, and so may be differently altered in depression and suicide. To investigate this, we compared the densities of GFAP-IR astrocytes and VIM-IR astrocytes in post-mortem brain samples from depressed suicides and matched non-psychiatric controls in three brain regions (dorsomedial prefrontal cortex, dorsal caudate nucleus and mediodorsal thalamus). A quantitative comparison of the fine morphology of VIM-IR astrocytes was also performed in the same regions and subjects. Finally, given the close association between astrocytes and blood vessels, we also assessed densities of CD31-IR blood vessels. Like for GFAP-IR astrocytes, VIM-IR astrocyte densities were found to be globally reduced in depressed suicides relative to controls. By contrast, CD31-IR blood vessel density and VIM-IR astrocyte morphometric features in these regions were similar between groups, except in prefrontal white matter, in which vascularization was increased and astrocytes displayed fewer primary processes. By revealing a widespread reduction of cerebral VIM-IR astrocytes in cases vs. controls, these findings further implicate astrocytic dysfunctions in depression and suicide.

Implication of cerebral astrocytes in major depression: A review of fine neuroanatomical evidence in humans

“…A previous study from our group found Golgi‐stained astrocytes in healthy individuals have a larger soma and simpler branch complexity (process numbers, nodes, and terminals) than VIM‐IR astrocytes, however, fibrous astrocytes had a comparable total process length (O'Leary et al, 2021; Torres‐Platas et al, 2011). We suspect the discrepancies in soma diameter and branch complexity for Golgi‐stained astrocytes relative to other studies is due to distortion from overimpregnation, and that process length differences may be a regional feature seen in proisocortex but not isocortex.…”

“…While altered astrocyte morphology has been previously reported for Golgi staining in the anterior cingulate cortical white matter of depressed suicides, this has not been observed for VIM‐IR astrocytes in four other areas of the brain which showed lower VIM‐IR astrocyte densities in depressed suicides (O'Leary et al, 2021; Torres‐Platas et al, 2011). As morphological changes are not widely apparent in brain regions which have reduced astrocyte densities and a lower expression of functional markers in MDD, it tentatively appears that astrocyte loss is a more reasonable interpretation for the decreased expression of astrocyte markers in MDD, rather than a state of reactive astrogliosis where most astrocyte genes with important functions are downregulated (Nagy et al, 2015; O'Leary et al, 2021; Torres‐Platas et al, 2016). The latter interpretation would contrast with currently known states of reactive astrogliosis characterized by an upregulation of VIM and GFAP and the potential for morphological changes and increased astrocyte signaling to other cell types (Escartin et al, 2021).…”

“…Postmortem studies have generally reported that healthy individuals have more GFAP‐IR astrocytes in cortical white matter than in cortical grey matter, and vice‐versa for VIM‐IR astrocytes in the same subject and regions (McNeal et al, 2016; O'Leary et al, 2020; O'Leary et al, 2021). Remarkably, VIM‐IR astrocytes are almost absent in the mediodorsal thalamus, a region where GFAP‐IR astrocytes are especially abundant in samples from the same subjects (O'Leary et al, 2020; O'Leary et al, 2021).…”

“…Postmortem studies have generally reported that healthy individuals have more GFAP-IR astrocytes in cortical white matter than in cortical grey matter, and vice-versa for VIM-IR astrocytes in the same subject and regions(McNeal et al, 2016;O'Leary et al, 2020;O'Leary et al, 2021). Remarkably, VIM-IR astrocytes are almost absent in the mediodorsal thalamus, a region where GFAP-IR astrocytes are especially abundant in samples from the same subjects(O'Leary et al, 2020;O'Leary et al, 2021).VIM and GFAP are often coexpressed in reactive astrocytes, yet VIM-IR and GFAP-IR astrocytes have heterogeneous densities in health and illness. While GFAP-IR astrocyte densities are generally reduced in depressed individuals, in the prefrontal cortex these changes vary for morphological subtype(Rajkowska et al, 2018).…”

Astrocytes in Post-traumatic Stress Disorder

“…2 ) [ 15 , 76 , 77 ]. Autopsy of suicides with depression shows a general decrease in the density of GFAP-positive astrocytes and vimentin-positive astrocytes in postmortem specimens from the dorsomedial prefrontal cortex, dorsal caudate nucleus, and medial thalamus, and a significant increase in the cluster of differentiation 31 (CD31)-positive vascularization in the white matter of the prefrontal cortex [ 78 ]. A detailed analysis of changes in the fine morphology of astrocytes and especially in leaflets contacting synapses is needed, as changes in these astrocytic structures are involved in the regulation of synaptic transmission [ 27 ].…”