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

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.

Keywords: PET imaging; depression; iMG cells; microglia; neuroinflammation; postmortem; suicide; tryptophan-kynurenine pathway.

Figure 1

Multi-dimensional approach to clarify the underlying roles of microglia in suicide. To clarify the underlying roles of human microglia in suicide, a multi-dimensional approach should be conducted. Brain neuropathological analysis and PET imaging are both essential in revealing direct pathophysiological evidence of microglia in suicide. Our 3D morphological analysis of microglia in a suicide victim is shown in the upper right. Our method is able to measure the 3D morphological parameter of the whole cell body and cell somata individually (details are shown in Supplementary Document). To overcome the limitations of brain studies in suicide, indirect non-brain approaches are also needed especially to grasp the dynamic roles of microglia in suicide and suicide-related behaviors including suicidal attempts/suicidal ideation. As indirect approaches, we propose the usage of peripheral bloods (plasma/serum and monocytes). Recently, dysregulation of the tryptophan-kynurenine pathway possibly via microglial activation has been suggested to be a positive link to suicide and suicide related behaviors. Novel key molecules, especially in the tryptophan/kynurenine pathway, may be discovered by wider analysis of metabolites, lipids and also neuron/microglia-derived exosomes in plasma/serum of suicidal patients. In addition, dynamic analysis of induced microglia-like (iMG) cells from blood monocytes is expected to reveal dynamic and molecular mechanisms of microglia in suicidal behaviors. Finally, deeper mechanisms of microglia in suicide may be discovered by the multi-dimensional combined analysis of both direct and indirect data. ACMSD, amino-β-carboxymuconate-semialdehyde-decarboxylase; HAAO, hydroxyanthranilate 3,4-dioxygenase; IDO, indoleamine 2,3-dioxygenases; KAT, kynurenine aminotransferases; KMO, kynurenine 3-monooxygenases; KYNU, kynureninase; TDO, tryptophan 2,3-dioxygenase; PET, positron emission tomography.