Suicide and Microglia: Recent Findings and Future Perspectives Based on Human Studies.

Hisaomi Suzuki,Nobuki Kuwano,Itaru Tominaga,Masahiro Ohgidani,Fabrice Chrétien,Dongchon Kang,Masaru Mimura,Takahiro A Kato,Daiki Setoyama,Mitsumoto Onaya,Shigenobu Kanba,Geoffroy Lorin De La Grandmaison

doi:10.3389/fncel.2019.00031

Abstract

Suicide is one of the most disastrous outcomes for psychiatric disorders. Recent advances in biological psychiatry have suggested a positive relationship between some specific brain abnormalities and specific symptoms in psychiatric disorders whose organic bases were previously completely unknown. Microglia, immune cells in the brain, are regarded to play crucial roles in brain inflammation by releasing inflammatory mediators and are suggested to contribute to various psychiatric disorders such as depression and schizophrenia. Recently, activated microglia have been suggested to be one of the possible contributing cells to suicide and suicidal behaviors via various mechanisms especially including the tryptophan-kynurenine pathway. Animal model research focusing on psychiatric disorders has a long history, however, there are only limited animal models that can properly express psychiatric symptoms. In particular, to our knowledge, animal models of human suicidal behaviors have not been established. Suicide is believed to be limited to humans, therefore human subjects should be the targets of research despite various ethical and technical limitations. From this perspective, we introduce human biological studies focusing on suicide and microglia. We first present neuropathological studies using the human postmortem brain of suicide victims. Second, we show recent findings based on positron emission tomography (PET) imaging and peripheral blood biomarker analysis on living subjects with suicidal ideation and/or suicide-related behaviors especially focusing on the tryptophan-kynurenine pathway. Finally, we propose future perspectives and tasks to clarify the role of microglia in suicide using multi-dimensional analytical methods focusing on human subjects with suicidal ideation, suicide-related behaviors and suicide victims.

Highlights

We should carefully interpret the data of microglia from postmortem brains especially in suicide victims because the time from death by suicide is not precisely calculated; (4) regional specificity should be analyzed; and (5) medication data should be considered as various in vitro studies using rodent microglial cells have suggested that some antipsychotics and antidepressants reduce microglial activation by suppressing the release of inflammatory mediators such as inflammatory cytokines and free radicals (Hashioka et al, 2007; Kato et al, 2007, 2008, 2011a,b; Bian et al, 2008; Horikawa et al, 2010; Hashioka, 2011; Müller et al, 2013; Su et al, 2015; Sato-Kasai et al, 2016)
On the other hand, using metabolomics, we have recently suggested the downregulation of this pathway is associated with the severity of suicidal ideation in depressed patients and/or firstepisode drug-naïve major depressive disorder (MDD) patients (Setoyama et al, 2016; Kuwano et al, 2018b)
A novel method has been developed to predict the levels of proteins which are related to neuron-derived exosomes (NDE) by analyzing small amounts of human blood plasma using a sandwich immunoassay between anti-neuron antibody and antibodies against CD81 and against other proteins related to neuroinflammation and synaptic functions (Kawata et al, 2018)

Summary

INTRODUCTION

Suicide is one of the most serious global mental health issues, and close to 900,000 people die due to suicide every year (Chesney et al, 2014). Microglial morphologies were significantly different (increased cell density and metamorphosis) in the brains of suicide victims These outcomes have suggested a relationship between microglial activation and suicide beyond the diagnostic classification of psychiatric disorders. We should carefully interpret the data of microglia from postmortem brains especially in suicide victims because the time from death by suicide is not precisely calculated; (4) regional specificity should be analyzed; and (5) medication data should be considered as various in vitro studies using rodent microglial cells have suggested that some antipsychotics and antidepressants reduce microglial activation by suppressing the release of inflammatory mediators such as inflammatory cytokines and free radicals (Hashioka et al, 2007; Kato et al, 2007, 2008, 2011a,b; Bian et al, 2008; Horikawa et al, 2010; Hashioka, 2011; Müller et al, 2013; Su et al, 2015; Sato-Kasai et al, 2016)

A PET STUDY FOCUSING ON MICROGLIA AND SUICIDE

ETHICS STATEMENT