Microglia, glial cells with immunological/inflammatory functions, have been suggested to play important roles in stress responses and various psychiatric disorders. To clarify physiological and pathological roles of microglia, novel translational approaches should be applied with a multi- dimensional approach toward psychology and psychiatry. 　In this article, we introduce recent rodent studies focusing on the relationship between stress and microglia. In addition, we introduce a novel translational research approach focusing on human microglia. Our recent neuroeconomic investigations with young healthy male volunteers using minocycline, an antibiotic with inhibitory effects on microglial activation, suggest that microglia may unconsciously modulate human social behaviors as “noise” under psychosocial stress. 　We believe that our novel translational approach will open the door to explore various unknown dynamic aspects of human microglia in the process of modulating the mind.

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The concepts of carbonyl stress (CS), oxidative stress (OS) and advanced glycation end products (AGEs) are the greatest feature of this research. Treatment-resistant schizophrenia (TRS) has consistent features by attempting to consolidate basic and clinical data on schizophrenia with CS presenting with depletion of vitamin B6 and accumulation of pentosidine, an AGE. The features and innovativeness of this research are in its reconsideration of pathologies that can be expanded from the “individual” to the “general” level. The research outcomes will be applied to drug development by establishing a new field of research in molecular psychiatry focused on CS, OS and AGEs. Data obtained from metabolic studies, genome research, cell models, animal models, and post-mortem brain research will be consolidated to elucidate genetic and environmental factors for psychological disorders, and the aggregated basic and clinical data will be consolidated and arranged in order to conduct research that makes appropriate use of “omics data” .

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Nonresolving low-grade inflammation is supposed to underly the basis of chronic disorders including cancer, type 2 diabete, cardiovascular diseases, obesity and psychiatric disorders such as depression. There is increasing evidence suggesting that pathophysiology of psychiatric disorders is related to the inflammatory responses mediated by microglial cells. Elevation of intracellular Ca²⁺ is important in activation of microglial cell functions, including proliferation, release of NO, cytokines and BDNF. It has been shown that alteration of intracellular Ca²⁺ signaling underlies the pathophysiology of psychiatric disorders, including schizophrenia, depression and bipolar disorders. Microglial cells are able to respond to BDNF, which may be important for the regulation of inflammator y responses, and may also be involved in the pathophysiology and/or the treatment of psychiatric disorders. In addition, we also need to examine the effect of proBDNF on microglial function.

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Accumulating evidence suggests that brain- derived neurotrophic factor (BDNF) and its receptor TrkB signaling plays a key role in the therapeutic mechanism of antidepressants. We found that BDNF-TrkB signaling was decreased in the prefrontal cortex and hippocampus from depressed rodents, whereas BDNF-TrkB signaling was increased in the nucleus accumbens from depressed rodents. TrkB agonist showed antidepressant effect via stimulation of TrkB signaling in the prefrontal cortex and hippocampus. In contrast, TrkB antagonist showed antidepressant effect via blockage of TrkB signaling in the nucleus accumbens. The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine shows rapid antidepressant effects in treatment- resistant patients with major depression and bipolar depression. Here the author would like to discuss the role of BDNF-TrkB- mTOR signaling in the therapeutic mechanism of antidepressants and ketamine.

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Group II metabotropic glutamate (mGlu) receptor antagonists exerted antidepressant effects in several animal models of depression including those refractory to currently prescribed antidepressants. Moreover, group II mGlu receptor antagonists exhibited rapid and sustained antidepressant effects in animal models, as observed in ketamine treatment. AMPA receptor stimulation and subsequent activation of BDNF-TrkB and mTOR signaling mediate antidepressant effects of group II mGlu receptor antagonists. In addition, group II mGlu receptor antagonists activate serotonin neurons in the dorsal raphe nucleus by stimulation of AMPA receptor in the medial prefrontal cortex to exert antidepressant effects. These molecular and neural mechanisms were shared by ketamine. Therefore, group II mGlu receptor antagonists may show rapid and sustained antidepressant effects for patients with treatment resistant depression.

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Mitochondrial permeability transition pore (mPTP) is a complex consists of multiple proteins; adenine nucleotide translocator (ANT) in the mitochondrial inner membrane, cyclophilin D (CypD) in the matrix, and the voltage - dependent anion channel (VDAC) in the mitochondrial outer membrane. Mitochondria take up Ca²⁺ via Ca²⁺ uniporters. When Ca²⁺ loading within mitochondrial matrix exceeds over their capacity, mPTP opens. The opening of mPTP is induced by binding of CypD and ANT. Deletion of CypD in mice enhanced mitochondrial Ca²⁺ uptake and improved symptoms of model animals of neurodegenerative diseases. In many types of animal models of neurodegenerative diseases, increased immobility time was obser ved in forced swimming test and tail suspension test. Additionally, patients with neurodegenerative diseases show a high prevalence of depressive symptoms and suicidal attempts. Thus, inhibition of mPTP opening will be a promising candidate for anti- depression treatment. These findings suggest that mPTP inhibitors might be promising as new therapeutic agents for depressive symptoms.

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We examined the relationships between plasma levels of fatty acids and biomarkers of AA-related signaling mediators (ceruloplasmin, transferrin and superoxide dismutase) with the behavioral and social symptoms of 21 individuals with ASD (mean age, 13.1 ± 4.5 years old) and 21 age-and gender-matched normal controls (mean age, 13.9 ± 5.7 years old). Behavioral and social symptoms were assessed using the Aberrant Behavior Checklists (ABC) and Social Responsiveness Scale (SRS) respectively. To compensate reduced plasma AA levels, the 21 individuals with ASD were treated with supplementation (precursor of omega-6 PUFAS, linoleic acid 480 mg/day plus omega-3 PUFA precursor α-linoleinic acid 240mg/day) for 16 weeks. Plasma EPA levels and arachidic acid, and the plasma ratios of eicosapentaenoic acid (EPA) /AA and docosahesaenoic acid (DHA) /AA were significantly higher while plasma levels of AA and ceruloplasmin (Cp) were significantly lower in the 21 individuals with ASD compared with the 21 controls. The ABC and SRS scores were significantly increased in the ASD group than in the control group. The 16-week treatment with AA supplementation significantly improved the four subscale scores ant total scores. In conclusion, this study firstly revealed that the reduced plasma levels of AA in association with high plasma EPA/AA ratio may down- regulate AA- related signaling mediator such as Cp. Thelowered Cp levels may reduce the protective capacity for the brain damage, causing in the pathophysiology underlying the core symptoms of individuals with ASD. Supplementation with higher doses of omega-6 fatty acid has therapeutic potential for the core ASD symptoms.

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Major depressive disorder (MDD) is a common disease that causes serious social impairments. However, a concordance rate of diagnosis for MDD on the basis of clinical symptoms is not high. To establish reliable diagnostic markers for MDD, which would contribute to early diagnosis and early treatment, is necessary. Although a number of studies have been conducted to identify biological markers for MDD, there are no objective clinical blood diagnostic markers for MDD at this point. We performed DNA methylation and gene expression profiling using blood to develop biological diagnostic tests for MDD, and we could differentiate patients with MDD from controls with good accuracy. Further efforts will be needed for clinical applications of these biological markers.

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