Distinct non-inflammatory signature of microglia in post-mortem brain tissue of patients with major depressive disorder

Snijders, Gijsje; Sneeboer, Marjolein A. M.; Fernández-Andreu, Alba; Udine, Evan; Boks, Marco P.; Ormel, Paul R.; Berlekom, Amber Berdenis van; Mierlo, Hans C. van; Böttcher, Chotima; Priller, Josef; Raj, Towfique; Hol, Elly M.; Kahn, René S.; Witte, Lot de

doi:10.1038/s41380-020-00896-z

Cited by 49 publications

(51 citation statements)

References 108 publications

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“…No alterations in inflammatory cytokine expression were detected in this study, suggesting increased microglial engagement in depression absent neuroinflammation. In line with this, recent transcriptomic analyses indicate a non-inflammatory, sensome-associated microglial signature in MDD ( Böttcher et al., 2020 ; Snijders et al., 2020 ). The ‘sensome’ represents a cluster of genes which aid microglia in ‘sensing’ changes in the brain microenvironment ( Hickman et al., 2013 ).…”

Section: Microglia Sex and Depression: Post-mortem Reports And Clinical Findingssupporting

confidence: 56%

Uncovering microglial pathways driving sex-specific neurobiological effects in stress and depression

Bollinger

2021

Brain, Behavior, & Immunity - Health

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Women suffer from major depressive disorder (MDD) more often than men and report greater MDD symptom severity. Mounting evidence suggests that sex differences in MDD may be driven, in part, by sex-specific neurobiological mechanisms. Chronic stress is a significant risk factor in MDD, and preclinical rodent models show differential patterns of stress-induced neural remodeling and cognitive-behavioral dysfunction in males and females. For instance, chronic stress leads to synapse loss in the medial prefrontal cortex in male rodents yet has either no effect on- or increases-synapse number in females. Recent reports have implicated microglia, the immune cells of the brain, in MDD, and findings demonstrate sex-specific microglial signatures in both preclinical stress models and MDD patients. Given that microglia can remodel neural architecture, modulate synaptic transmission, and affect subsequent changes in behavior, it is plausible that microglial pathways contribute to differential stress effects on neuroplasticity and function in males and females. As such, this review examines the evidence for sex-specific microglia-neuron interactions in preclinical stress models and in patients with MDD. Discoveries highlighted herein demonstrate divergent microglial contributions in males and females and suggest that future studies investigating stress-linked disorders should be guided by sex-dependent neurobiological and behavioral findings. Examining these pathways represents a clear avenue toward both a richer understanding of brain, behavior, and immunity, and innovative psychoneuroimmunology-based applications in personalized medicine.

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Section: Microglia Sex and Depression: Post-mortem Reports And Clinical Findingssupporting

confidence: 56%

Uncovering microglial pathways driving sex-specific neurobiological effects in stress and depression

Bollinger

2021

Brain, Behavior, & Immunity - Health

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“…Except for a decreased expression of CD44, we found no indications for SCZ‐associated changes in infiltrating macrophages (Table S15). Analyses at the single‐cell level, such as mass cytometry (Böttcher et al, 2019; Sneeboer et al, 2019; Snijders et al, 2020) or single nuclei RNA‐seq (Masuda et al, 2020; Mathys et al, 2019) are needed to further understand how the composition of myeloid cells is changed in schizophrenia.…”

Section: Discussionmentioning

confidence: 99%

A loss of mature microglial markers without immune activation in schizophrenia

Snijders

Zuiden

Sneeboer³

et al. 2021

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Microglia, the immune cells of the brain, are important for neurodevelopment and have been hypothesized to play a role in the pathogenesis of schizophrenia (SCZ). Although previous postmortem studies pointed toward presence of microglial activation, this view has been challenged by more recent hypothesis‐driven and hypothesis‐free analyses. The aim of the present study is to further understand the observed microglial changes in SCZ. We first performed a detailed meta‐analysis on studies that analyzed microglial cell density, microglial morphology, and expression of microglial‐specific markers. We then further explored findings from the temporal cortex by performing immunostainings and qPCRs on an additional dataset. A random effect meta‐analysis showed that the density of microglial cells was unaltered in SCZ (ES: 0.144 95% CI: 0.102 to 0.390, p = .250), and clear changes in microglial morphology were also absent. The expression of several microglial specific genes, such as CX3CR1, CSF1R, IRF8, OLR1, and TMEM119 was decreased in SCZ (ES: −0.417 95% CI: −0.417 to −0.546, p < .0001), consistent with genome‐wide transcriptome meta‐analysis results. These results indicate a change in microglial phenotype rather than density, which was validated with the use of TMEM119/Iba1 immunostainings on temporal cortex of a separate cohort. Changes in microglial gene expression were overlapping between SCZ and other psychiatric disorders, but largely opposite from changes reported in Alzheimer's disease. This distinct microglial phenotype provides a crucial molecular hallmark for future research into the role of microglia in SCZ and other psychiatric disorders.

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“…The elevated translocator protein (TSPO) binding assessed by positron emission tomography studies in various brain regions of depressed patients backs microglial activation (Setiawan et al, 2015;Owen et al, 2017). Also, studies using other markers of microglial activation, such as Iba-1 or quinolinic acid, have found increased microglial reactivity in depression, whereas no difference between the density of major histocompatibility complex (HLA)-immunoreactive microglia in post-mortem brain samples of depressed subjects (Hamidi et al, 2004;Snijders et al, 2020). A recent study using single-cell high-dimensional mass cytometry (CyTOF) examined microglia from post-mortem MDD samples from different brain regions and found increased markers of homeostatic microglia, including transmembrane protein (TMEM)119 and P2Y12 in MDD compared to controls, which is in clear contrast with what has been found in animal studies (Bottcher et al, 2020).…”

Section: Findings In Human Depression Studiesmentioning

confidence: 99%

Neuroinflammatory Basis of Depression: Learning From Experimental Models

Suk

2021

Front. Cell. Neurosci.

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The neuroinflammatory basis of depression encompasses the detrimental role of otherwise supportive non-neuronal cells and neuroinflammation in hampering neuronal function, leading to depressive behavior. Animals subjected to different stress paradigms show glial cell activation and a surge in proinflammatory cytokines in various brain regions. The concept of sterile inflammation observed in animal models of depression has intrigued many researchers to determine the possible triggers of central immune cell activation. Notably, microglial activation and subsequent phenotypic polarization in depression have been strongly advocated by the wealth of recent preclinical studies; however, findings from human studies have shown contradictory results. Despite intensive investigation, many research gaps still exist to elucidate the molecular mechanisms of neuroinflammatory cascades underlying the pathophysiology of depression. In this mini-review, recent progress in understanding neuroinflammatory mechanisms in light of experimental models of depression will be thoroughly discussed. The challenges of mirroring depression in animal and in vitro models will also be highlighted. Furthermore, prospects of targeting neuroinflammation to treat depressive disorder will be covered.

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Distinct non-inflammatory signature of microglia in post-mortem brain tissue of patients with major depressive disorder

Cited by 49 publications

References 108 publications

Uncovering microglial pathways driving sex-specific neurobiological effects in stress and depression

Uncovering microglial pathways driving sex-specific neurobiological effects in stress and depression

A loss of mature microglial markers without immune activation in schizophrenia

Neuroinflammatory Basis of Depression: Learning From Experimental Models

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