Microglia in the dorsal raphe nucleus plays a potential role in both suicide facilitation and prevention in affective disorders

Abstract

An involvement of the central serotonergic system has constantly been reported in the pathogenesis of suicide. The dorsal raphe nucleus (DRN) is the main source of serotonergic innervation of forebrain limbic structures disturbed in suicidal behaviour, in which an abnormal microglia reaction seems to play a role. In our present study, the density of microglia immunostained for the HLA-DR antigen was evaluated in the DRN. These analyses were carried out on paraffin-embedded brains from 24 suicidal and 21 non-suicidal patients; among them, 27 depressed (15 major depressive disorder and 12 bipolar disorder) and 18 schizophrenia (9 residual and 9 paranoid) patients and 22 matched controls without mental disorders. Only the non-suicidal depressed subgroup revealed significantly lower microglial reaction, i.e., a decreased density of HLA-DR positive microglia versus both depressed suicide victims and controls. The effect was not related to antidepressant or antipsychotic medication, as the former correlated positively with microglial density in non-suicidal depressed patients, and the latter had no effect. Moreover, the comparison of these results with previously published data from our workgroup in the same cohort (Krzyżanowska et al. in Psychiatry Res 241:43–46, 4) suggested a positive impact of microglia on ribosomal DNA transcription in DRN neurons in the non-suicidal depressed subgroup, but not in depressed suicidal cases. Therefore, the interaction between microglia and neurons in the DRN may be potentially involved in opposite ways regarding suicide facilitation and prevention in the tested subgroups of depressed patients.

Elevated Translocator Protein in Anterior Cingulate in Major Depression and a Role for Inflammation in Suicidal Thinking: A Positron Emission Tomography Study

“…We cannot necessarily conclude that neuroinflammation is absent in those with normal or lowered TSPO as increased levels of inflammatory cytokines can occur with a downregulation (rather than upregulation) of TSPO (72). Nevertheless, the pattern of TSPO availability in our patients is consistent with recent postmortem findings of significantly decreased microglial activation in non-suicidal depressed patients compared to suicidal depressed patients and controls in the dorsal raphe nucleus, which provides the major serotonergic innervation to the ACC, PFC and insula (48). This is particularly interesting given recent evidence that abnormal 5-HT function measured using PET predicts higher suicidal ideation and more lethal suicidal behavior (80).…”

“…Furthermore, a higher degree of suicidal ideation has been associated with an increased inflammatory index, independent of severity of depressive symptoms (45). Multiple postmortem studies have found evidence for inflammation in the brains of suicide victims (46,47), with specific evidence for activated microglia in the ACC and PFC of depressed individuals who had committed suicide (32,33), and significantly less microglial activation in the dorsal raphe nucleus in non-suicidal depressed patients who had died of other causes compared to suicidal depressed patients and controls (48). However, no study to date has investigated the association between neuroinflammation and suicidality in depression in-vivo.…”

Single-Cell Analysis of Neuroinflammatory Responses Following Intracranial Injection of G-Deleted Rabies Viruses

“…Recent studies have found significant associations between genes with known immune functions and diseases that include Alzheimer's Disease and schizophrenia (Sekar et al, 2016;Henstridge et al, 2019;Kunkle et al, 2019;Mathys et al, 2019). Pro-inflammatory signaling and immunological perturbations in the dorsal raphe nucleus (DRN), the largest serotonergic center in the brain, have also been implicated in behavioral and mood disorders that include impulsivity, major depressive disorder, and bipolar disorder (Mahmood and Silverstone, 2001;Baumann et al, 2002;Matthews and Harrison, 2012;Howerton et al, 2014;Brisch et al, 2017). Microglia, the predominant resident immune cells of the central nervous system (CNS), express many of these disease-associated genes and undergo transcriptional changes and diversification in both acute and chronic models of inflammation, aging, and neurodegeneration (Mrdjen et al, 2018;Hammond et al, 2019;Jordão et al, 2019;Li et al, 2019).…”

Resilience Dysregulation in Major Depressive Disorder: Focus on Glutamatergic Imbalance and Microglial Activation

“…Microglia cells have been shown to play an important role in the pathophysiology of MDD [ 25 , 140 ]. Additionally, the status of microglial activation and inflammation also appear to be associated with stress vulnerability and resilience.…”