Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2020 Aug 11:11:781.
doi: 10.3389/fpsyt.2020.00781. eCollection 2020.

Microglial Dysregulation and Suicidality: A Stress-Diathesis Perspective

Affiliations
Review

Microglial Dysregulation and Suicidality: A Stress-Diathesis Perspective

Paria Baharikhoob et al. Front Psychiatry. .

Abstract

According to the stress-diathesis model of suicidal behavior, completed suicide depends on the interaction between psychosocial stressors and a trait-like susceptibility. While there are likely multiple biological processes at play in suicidal behavior, recent findings point to over-activation of microglia, the resident macrophages of the central nervous system, as implicated in stress-induced suicidal behavior. However, it remains unclear how microglial dysregulation can be integrated into a clinical model of suicidal behavior. Therefore, this narrative review aims to (1) examine the findings from human post-mortem and neuroimaging studies that report a relationship between microglial activation and suicidal behavior, and (2) update the clinical model of suicidal behavior to integrate the role of microglia. A systematic search of SCOPUS, PubMed, PsycINFO, and Embase databases revealed evidence of morphological alterations in microglia and increased translocator protein density in the brains of individuals with suicidality, pointing to a positive relationship between microglial dysregulation and suicidal behavior. The studies also suggested several pathological mechanisms leading to suicidal behavior that may involve microglial dysregulation, namely (1) enhanced metabolism of tryptophan to quinolinic acid through the kynurenine pathway and associated serotonin depletion; (2) increased quinolinic acid leading to excessive N-methyl-D-aspartate-signaling, resulting in potential disruption of the blood brain barrier; (3) increased quinolinic acid resulting in higher neurotoxicity, and; (4) elevated interleukin 6 contributing to loss of inhibition of glutamatergic neurons, causing heightened glutamate release and excitotoxicity. Based on these pathways, we reconceptualized the stress-diathesis theory of suicidal behavior to incorporate the role of microglial activity.

Keywords: microglia; neuroinflammation; positron emission tomography; post-mortem; stress-diathesis model; suicide.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Flowchart for the inclusion of appropriate original articles. This flowchart showcases the selection process for the inclusion of articles for review according to the PRISMA statement (66).
Figure 2
Figure 2
Reconceptualized clinical model of SB incorporating microglial dysregulation. This model proposes that prolonged psychosocial stress leads to the over-activation of microglia and associated release of pro-inflammatory cytokines. The release of pro-inflammatory cytokines stimulates the shift from serotonin to KYN synthesis through the induction of IDO1. This shift results in the depletion of serotonin. The production of QUIN from KYN synthesis, in addition, increases neurotoxicity. Moreover, increased QUIN production directly leads to heightened glutamate release and associated excitotoxicity but also indirectly causes this elevation by increasing IL-6 levels. Increased glutamate release and excitotoxicity contribute to the disruption of the BBB. Altogether, all these mechanisms contribute to behavioral manifestations, which may then result in SB and/or death by suicide. This figure was created with BioRender.com. BBB, blood brain barrier; IDO1, indoleamine 2,3-dioxygenase; IFN-γ, interferon gamma; IL-1β, interleukin-1β; IL-6, interleukin-6; NOX2, NADPH oxidase; KYN, kynurenine; QUIN, quinolinic acid; ROS, reactive oxygen species; SB, suicidal behavior; TNF-α, tumor necrosis factor-α; TRY, tryptophan.

References

    1. Mann JJ, Waternaux C, Haas GL, Malone KM. Toward a clinical model of suicidal behavior in psychiatric patients. Am J Psychiatry (1999) 156(2):181–9. 10.1176/ajp.156.2.181 - DOI - PubMed
    1. Mann JJ. Neurobiology of suicidal behaviour. Nat Rev Neurosci (2003) 4(10):819–28. 10.1038/nrn1220 - DOI - PubMed
    1. Benedetti F, Riccaboni R, Poletti S, Radaelli D, Locatelli C, Lorenzi C, et al. The serotonin transporter genotype modulates the relationship between early stress and adult suicidality in bipolar disorder. Bipolar Disord (2014) 16(8):857–66. 10.1111/bdi.12250 - DOI - PubMed
    1. Gibb BE, McGeary JE, Beevers CG, Miller IW. Serotonin transporter (5-HTTLPR) genotype, childhood abuse, and suicide attempts in adult psychiatric inpatients. Suicide Life Threat Behav (2006) 36(6):687–93. 10.1521/suli.2006.36.6.687 - DOI - PubMed
    1. Roy A, Hu X-Z, Janal MN, Goldman D. Interaction between childhood trauma and serotonin transporter gene variation in suicide. Neuropsychopharmacology (2007) 32(9):2046–52. 10.1038/sj.npp.1301331 - DOI - PubMed

LinkOut - more resources