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Microglia are intrinsic immune cells that release factors including pro- and anti-inflammatory cytokines, nitric oxide (NO) and neurotrophins following activation in the brain. Elevation of intracellular Ca2+ concentration ([Ca2+ ]i) is important for microglial functions, such as the release of cytokines or NO from activated microglia. Brain-derived neurotrophic factor (BDNF) is a neurotrophin well known for its roles in the activation of microglia. Interestingly, proBDNF, the precursor form of mature BDNF, and mature BDNF elicit opposing neuronal responses in the brain. Mature BDNF induces sustained intracellular Ca2+ elevation through the upregulation of the surface expression of TRPC3 channels in rodent microglial cells. In addition, TRPC3 channels are important for the BDNF-induced suppression of NO production in activated microglia. In this study, we observed that proBDNF and mature BDNF have opposite effects on the relative expression of surface p75 neurotrophin receptor (p75NTR ) in rodent microglial cells. ProBDNF induces a sustained elevation of [Ca2+ ]i through binding to the p75NTR , which is possibly mediated by Rac 1 activation and TRPM7 channels in rodent microglial cells. Flow cytometry showed that proBDNF increased the relative surface expression of TRPM7. Although proBDNF did not affect either mRNA expression of pro- and anti-inflammatory cytokines or the phagocytic activity, proBDNF potentiates the generation of NO induced by IFN-γ and TRPM7 channels could be involved in the proBDNF-induced potentiation of IFN-γ-mediated production of NO. We show direct evidence that rodent microglial cells are able to respond to proBDNF, which might be important for the regulation of inflammatory responses in the brain.

Aim The impairment experienced by many individuals with depression is closely related to the cognitive symptoms of the disorder. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation method providing a promising technique for improving cognitive symptoms in treatment-resistant depression (TRD). In the present study, we investigated whether a relationship exists between improvements in frontal lobe dysfunction induced by rTMS and improvement of white matter integrity revealed by diffusion tensor imaging (DTI) in TRD patients receiving rTMS treatment. Methods A total of 12 patients with TRD were enrolled in a high-frequency (10 Hz) rTMS study (August 2013-January 2019). Frontal lobe function and depressive symptoms were assessed at baseline and at the endpoint of rTMS treatment. Fractional anisotropy (FA), as a measure of white matter integrity obtained from DTI, was investigated using a region-of-interest (ROI) approach. Results rTMS treatment significantly improved depressive symptom scores and some subscales of frontal lobe dysfunction. Category scores in the Word Fluency Test and scores on part 3 of the Color Stroop Test were improved independently of the improvement of depressive symptoms. In the ROI analysis, none of the FA increases in any region were correlated with improvement of any frontal lobe function (n = 12). Conclusion Although rTMS resulted in partial improvement of frontal lobe dysfunction as well as white matter integrity, we found no correlation between improved frontal lobe dysfunction and improved white matter integrity in TRD patients.

Lithium administration can reportedly cause toxicity, including lithium-associated thrombosis; however, not all reported cases of this adverse effect have been attributable to lithium overdoses. We report here two cases of deep vein thrombosis that occurred in association with lithium toxicity. Lithium overdose was deemed to be the cause in only one of these cases; a patient in whom deep vein thrombosis occurred 11 days after identification of lithium toxicity. In the other patient, the deep vein thrombosis occurred 15 days after diagnosis of lithium toxicity; this patient was not considered to have been overdosed. Both patients had other risk factors in addition to receiving lithium. We recommend monitoring D-dimer concentrations to facilitate early detection of deep vein thrombosis in patients with lithium toxicity.

The pathophysiology of Alzheimer’s disease (AD) is related to neuroinflammatory responses mediated by microglia. Memantine, an antagonist of N-methyl-d-aspartate (NMDA) receptors used as an anti-Alzheimer’s drug, protects from neuronal death accompanied by suppression of proliferation and activation of microglial cells in animal models of AD. However, it remains to be tested whether memantine can directly affect microglial cell function. In this study, we examined whether pretreatment with memantine affects intracellular NO and Ca2+ mobilization using DAF-2 and Fura-2 imaging, respectively, and tested the effects of memantine on phagocytic activity by human β-Amyloid (1–42) phagocytosis assay in rodent microglial cells. Pretreatment with memantine did not affect production of NO or intracellular Ca2+ elevation induced by TNF in rodent microglial cells. Pretreatment with memantine also did not affect the mRNA expression of pro-inflammatory (TNF, IL-1β, IL-6 and CD45) or anti-inflammatory (IL-10, TGF-β and arginase) phenotypes in rodent microglial cells. In addition, pretreatment with memantine did not affect the amount of human β-Amyloid (1–42) phagocytosed by rodent microglial cells. Moreover, we observed that pretreatment with memantine did not affect 11 major proteins, which mainly function in the phagocytosis and degradation of β-Amyloid (1–42), including TREM2, DAP12 and neprilysin in rodent microglial cells. To the best of our knowledge, this is the first report to suggest that memantine does not directly modulate intracellular NO and Ca2+ mobilization or phagocytic activity in rodent microglial cells. Considering the neuroinflammation hypothesis of AD, the results might be important to understand the effect of memantine in the brain.

Schizophrenia develops mainly in adolescence, but late-onset schizophrenia (LOS) is not uncommon. According to the international consensus, schizophrenia which develops over 40 years old is called LOS and psychosis which develops over 60 years old is called very late-onset schizophrenia-like psychosis (VLOS). Compared to early-onset schizophrenia (EOS) that develops before the age of 40 years, LOS and VLOS are reported to be more common in women, and there are clinically clear differences such as less involvement of genetic factors than EOS. This review outlines the abnormalities of the neuroimmune system in the pathophysiology of LOS, especially focusing on the role of microglia.

Background Microglia are resident innate immune cells which release many factors including proinflammatory cytokines or nitric oxide (NO) when they are activated in response to immunological stimuli. Pathophysiology of Alzheimer’s disease (AD) is related to the inflammatory responses mediated by microglia. Intracellular Ca2+ signaling is important for microglial functions such as release of NO and cytokines. In addition, alteration of intracellular Ca2+ signaling underlies the pathophysiology of AD, while it remains unclear how donepezil, an acetylcholinesterase inhibitor, affects intracellular Ca2+ mobilization in microglial cells. Methods We examined whether pretreatment with donepezil affects the intracellular Ca2+ mobilization using fura-2 imaging and tested the effects of donepezil on phagocytic activity by phagocytosis assay in rodent microglial cells. Results In this study, we observed that pretreatment with donepezil suppressed the TNFα-induced sustained intracellular Ca2+ elevation in both rat HAPI and mouse primary microglial cells. On the other hand, pretreatment with donepezil did not suppress the mRNA expression of both TNFR1 and TNFR2 in rodent microglia we used. Pretreatment with acetylcholine but not donepezil suppressed the TNFα-induced intracellular Ca2+ elevation through the nicotinic α7 receptors. In addition, sigma 1 receptors were not involved in the donepezil-induced suppression of the TNFα-mediated intracellular Ca2+ elevation. Pretreatment with donepezil suppressed the TNFα-induced intracellular Ca2+ elevation through the PI3K pathway in rodent microglial cells. Using DAF-2 imaging, we also found that pretreatment with donepezil suppressed the production of NO induced by TNFα treatment and the PI3K pathway could be important for the donepezil-induced suppression of NO production in rodent microglial cells. Finally, phagocytosis assay showed that pretreatment with donepezil promoted phagocytic activity of rodent microglial cells through the PI3K but not MAPK/ERK pathway. Conclusions These suggest that donepezil could directly modulate the microglial function through the PI3K pathway in the rodent brain, which might be important to understand the effect of donepezil in the brain. Electronic supplementary material The online version of this article (10.1186/s12974-017-1033-0) contains supplementary material, which is available to authorized users.

Oxytocin is deeply involved in human relations. In recent years, it is becoming clear that oxytocin is also involved in social cognition and social behaviour. Oxytocin receptors are also thought to be present in the hippocampus and amygdala, and the relationship between oxytocin and the structure and function of the hippocampus and amygdala has been reported. However, a few studies have investigated oxytocin and its relationship to hippocampus and amygdala volume in elderly people. The aim of this study is to investigate the association between serum oxytocin levels and hippocampus and amygdala volume in elderly people. The survey was conducted twice in Kurokawa-cho, Imari, Saga Prefecture, Japan, among people aged 65 years and older. We collected data from 596 residents. Serum oxytocin level measurements, brain MRI, Mini–Mental State Examination and Clinical Dementia Rating were performed in Time 1 (2009–11). Follow-up brain MRI, Mini–Mental State Examination and Clinical Dementia Rating were performed in Time 2 (2016–17). The interval between Time 1 and Time 2 was about 7 years. Fifty-eight participants (14 men, mean age 72.36 ± 3.41 years, oxytocin 0.042 ± 0.052 ng/ml; 44 women, mean age 73.07 ± 4.38 years, oxytocin 0.123 ± 0.130 ng/ml) completed this study. We analysed the correlation between serum oxytocin levels (Time 1) and brain volume (Time 1, Time 2 and Times 1–2 difference) using voxel-based morphometry implemented with Statistical Parametric Mapping. Analysis at the cluster level (family-wise error; P, The aim of this study is to investigate the association between serum oxytocin levels and hippocampus and amygdala volume in elderly people. Oxytocin levels in people aged 65 years and older may be associated with aging-related changes in hippocampus and amygdala volume., Graphical Abstract Graphical Abstract

Aim Electroconvulsive therapy (ECT) is effective for psychiatric disorders. However, its action mechanism remains unclear. We previously reported that transcription factor 7 (TCF7) was increased in patients successfully treated with ECT. TCF7 regulates Wnt pathway, which regulates adult hippocampal neurogenesis. Adult hippocampal neurogenesis is involved in the pathophysiology of psychiatric disorders. Astrocytes play a role in adult hippocampal neurogenesis via neurogenic factors. Of astrocyte-derived neurogenic factors, leukemia inhibitory factor (LIF) and fibroblast growth factor 2 (FGF2) activate Wnt pathway. In addition, adenosine triphosphate (ATP), released from excited neurons, activates astrocytes. Therefore, we hypothesized that ECT might increase LIF and/or FGF2 in astrocytes. To test this, we investigated the effects of ATP and electric stimulation (ES) on LIF and FGF2 expressions in astrocytes. Methods Astrocytes were derived from neonatal mouse forebrain and administered ATP and ES. The mRNA expression was estimated with quantitative reverse-transcription polymerase chain reaction. Protein concentration was measured with ELISA. Results ATP increased LIF, but not FGF2, expression. Multiple ES, but not single, increased LIF expression. Knockdown of P2X2 receptor (P2X2R) attenuated ATP-induced increase of LIF mRNA expression. In contrast, P2X3 and P2X4 receptors intensified it. Conclusion P2X2R may mediate ATP-induced LIF expression in astrocytes and multiple ES directly increases LIF expression in astrocytes. Therefore, both ATP/P2X2R and multiple ES-induced increases of LIF expression in astrocytes might mediate the efficacy of ECT on psychiatric disorders. Elucidating detailed mechanisms of ATP/P2X2R and multiple ES-induced LIF expression is expected to result in the identification of new therapeutic targets for psychiatric disorders.

Viral infections during fetal and adolescent periods, as well as during the course of schizophrenia itself have been linked to the onset and/or relapse of a psychosis. We previously reported that the unique antipsychotic aripiprazole, a partial D2 agonist, inhibits the release of tumor necrosis factor (TNF)-α from interferon-γ-activated rodent microglial cells. Polyinosinic-polycytidylic acid (polyI:C) has recently been used as a standard model of viral infections, and recent in vitro studies have shown that microglia are activated by polyI:C. Aripiprazole has been reported to ameliorate behavioral abnormalities in polyI:C-induced mice. To clarify the anti-inflammatory properties of aripiprazole, we investigated the effects of aripiprazole on polyI:C-induced microglial activation in a cellular model of murine microglial cells and possible surrogate cells for human microglia. PolyI:C treatment of murine microglial cells activated the production of TNF-α and enhanced the p38 mitogen-activated protein kinase (MAPK) pathway, whereas aripiprazole inhibited these responses. In addition, polyI:C treatment of possible surrogate cells for human microglia markedly increased TNF-α mRNA expression in cells from three healthy volunteers. Aripiprazole inhibited this increase in cells from two individuals. PolyI:C consistently increased intracellular Ca2+ concentration ([Ca2+]i) in murine microglial cells by influx of extracellular Ca2+. We demonstrated that transient receptor potential in melastatin 7 (TRPM7) channels contributed to this polyI:C-induced increase in [Ca2+]i. Taken together, these data suggest that aripiprazole may be therapeutic for schizophrenia by reducing microglial inflammatory reactions, and TRPM7 may be a novel therapeutic target for schizophrenia. Further studies are needed to validate these findings.

Microglia have recently been highlighted to understand the pathophysiology of various psychiatric disorders including depression. In this brief review article, we have shown up-to-date knowledge about the effects of psychotropic drugs, especially aripiprazole, on microglial modulation and the relationship between microglia and neurotransmitters such as serotonin and noradrenaline, to understand the cross talk between microglia and neuronal systems. Finally, we have introduced a novel translational research tool, induced microglia-like (iMG) cells from human peripheral blood (monocytes). Further translational studies combining human tissue studies and animal experiences are needed to dig up the microglial roles in the underlying biological mechanisms of depression and other psychiatric disorders.

Autism spectrum disorders (ASDs) are neurodevelopmental disorders characterized by deficits in social interaction, difficulties with language and repetitive/restricted behaviors. Microglia are resident innate immune cells which release many factors including proinflammatory cytokines, nitric oxide (NO) and brain-derived neurotrophic factor (BDNF) when they are activated in response to immunological stimuli. Recent in vivo imaging has shown that microglia sculpt and refine the synaptic circuitry by removing excess and unwanted synapses and be involved in the development of neural circuits or synaptic plasticity thereby maintaining the brain homeostasis. BDNF, one of the neurotrophins, has various important roles in cell survival, neurite outgrowth, neuronal differentiation, synaptic plasticity and the maintenance of neural circuits in the CNS. Intracellular Ca2+ signaling is important for microglial functions including ramification, de-ramification, migration, phagocytosis and release of cytokines, NO and BDNF. BDNF induces a sustained intracellular Ca2+ elevation through the upregulation of the surface expression of canonical transient receptor potential 3 (TRPC3) channels in rodent microglia. BDNF might have an anti-inflammatory effect through the inhibition of microglial activation and TRPC3 could play important roles in not only inflammatory processes but also formation of synapse through the modulation of microglial phagocytic activity in the brain. This review article summarizes recent findings on emerging dual, inflammatory and non-inflammatory, roles of microglia in the brain and reinforces the importance of intracellular Ca2+ signaling for microglial functions in both normal neurodevelopment and their potential contributing to neurodevelopmental disorders such as ASDs.

We previously reported that the addition of orally administered yokukansan (YKS), a traditional Japanese herbal medicine, to the standard regimen using histamine H1-receptor inhibitors was effective in controlling refractory chronic urticaria, but the mechanism remained unknown. YKS has also been reported to be effective on inhibiting the development of atopic dermatitis-like skin lesions in NC/Nga mice. As known, the release of various chemical mediators including histamine from degranulated mast cells is strongly related to the mechanism of these diseases. Thus the purpose of this study was to examine the mechanisms behind the medicinal effects of YKS on mast cells using an in vitro system and rat basophil leukemia (RBL-2H3) cells. The degree of degranulation was measured by β-hexosaminidase secretion assay and intracellular calcium influx assay. ELISA for cytokines (TNF-α and IL-4) was also conducted using cell culture media. Furthermore, we investigated the effects of YKS on the expression of adhesion molecules (ICAM-1, VCAM-1, E-selectin) and cytokine production (IL-8) in human dermal microvascular endothelial cells using gene-transcriptional- and immunohisotoligical analysis. We found that YKS inhibited secretion of β-hexosaminidase, intracellular calcium increase, production of TNF-α and ICAM-1 expression, and that several YKS ingredients may be the key effectors. In conclusion, YKS may suppress several mast cell functions such as degranulation and calcium increase that eventually inhibits the release of proinflammatory cytokines. Furthermore, YKS suppresses ICAM-1 expression on human microvascular endothelial cells. These findings may promote our understanding of the beneficial effects of YKS on mast cell-associated allergic diseases.

Microglia are immune cells that release factors, including proinflammatory cytokines, nitric oxide (NO), and neurotrophins, following activation after disturbance in the brain. Elevation of intracellular Ca(2+) concentration ([Ca(2+)]i) is important for microglial functions such as the release of cytokines and NO from activated microglia. There is increasing evidence suggesting that pathophysiology of neuropsychiatric disorders is related to the inflammatory responses mediated by microglia. Brain-derived neurotrophic factor (BDNF) is a neurotrophin well known for its roles in the activation of microglia as well as in pathophysiology and/or treatment of neuropsychiatric disorders. In this study, we sought to examine the underlying mechanism of BDNF-induced sustained increase in [Ca(2+)]i in rodent microglial cells. We observed that canonical transient receptor potential 3 (TRPC3) channels contribute to the maintenance of BDNF-induced sustained intracellular Ca(2+) elevation. Immunocytochemical technique and flow cytometry also revealed that BDNF rapidly up-regulated the surface expression of TRPC3 channels in rodent microglial cells. In addition, pretreatment with BDNF suppressed the production of NO induced by tumor necrosis factor α (TNFα), which was prevented by co-adiministration of a selective TRPC3 inhibitor. These suggest that BDNF induces sustained intracellular Ca(2+) elevation through the up-regulation of surface TRPC3 channels and TRPC3 channels could be important for the BDNF-induced suppression of the NO production in activated microglia. We show that TRPC3 channels could also play important roles in microglial functions, which might be important for the regulation of inflammatory responses and may also be involved in the pathophysiology and/or the treatment of neuropsychiatric disorders.

An accumulating body of evidence point to the significance of neuroinflammation and immunogenetics also in schizophrenia. Recent genome-wide studies in schizophrenia suggest immune involvement in schizophrenia. Microglia are the resident macrophage of the brain and major players in innate immunity in the CNS. They respond rapidly to even minor pathological changes in the brain and may contribute directly to the neuronal degeneration by producing various pro-inflammatory cytokines and free radicals. In many aspects, the neuropathology of schizophrenia is closely associated with microglial activation. We and other researchers have shown the inhibitory effects of some typical or atypical antipsychotics on the release of inflammatory cytokines and free radicals from activated microglia, both of which are not only directly toxic to neurons but also cause a decrease in neurogenesis as well as white matter abnormalities in the brains of the patients with schizophrenia. The treatment through the inhibition of microglial activation may shed new light on the therapeutic strategy of schizophrenia.

The pathophysiology of bipolar disorder, especially the underlying mechanisms of the bipolarity between manic and depressive states, has yet to be clarified. Microglia, immune cells in the brain, play important roles in the process of brain inflammation, and recent positron emission tomography (PET) studies have indicated microglial over-activation in the brain of patients with bipolar disorder. We have recently developed a technique to induce human microglia-like (iMG) cells from peripheral blood (monocytes). We introduce a novel translational approach focusing on bipolar disorder using this iMG technique. We hypothesize that immunological conditional changes in microglia may contribute to the shift between manic and depressive states, and thus we herein analyzed gene profiling patterns of iMG cells from three patients with rapid cycling bipolar disorder during both manic and depressive states, respectively. We revealed that the gene profiling patterns are different between manic and depressive states. The profiling pattern of case 1 showed that M1 microglia is dominant in the manic state compared to the depressive state. However, the patterns of case 2 and 3 were not consistent with the pattern of case 1. CD206, a mannose receptor known as a typical M2 marker, was significantly downregulated in the manic state among all three patients. This is the first report to indicate the importance of shifting microglial M1/M2 characteristics, especially the CD206 gene expression pattern between depressive and manic states. Further translational studies are needed to dig up the microglial roles in the underlying biological mechanisms of bipolar disorder.

Nonresolving low-grade inflammation is supposed to underly the basis of chronic disorders including cardiovascular diseases, cancer, diabetes, obesity, and psychiatric disorders such as depression and Alzheimer’s diseases. 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 for the 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 depression. BDNF induces a sustained intracellular Ca2+ elevation through the upregulation of the surface expression of TRPC3 channels in rodent microglial cells. Microglial cells are able to respond to BDNF, which may be important for the regulation of inflammatory responses and may also be involved in the pathophysiology and/or the treatment of psychiatric disorders. We also need to study the effect of proBDNF on microglial cells especially by focusing on the TRPC channels.

Altered antioxidant status has been implicated in schizophrenia. Microglia, major sources of free radicals such as superoxide (•O(2)(-)), play crucial roles in various brain pathologies. Recent postmortem and imaging studies have indicated microglial activation in the brain of schizophrenic patients. We previously demonstrated that atypical antipsychotics including aripiprazole significantly inhibited the release of nitric oxide and proinflammatory cytokines from interferon-γ-stimulated microglia in vitro. Antioxidative effects of antipsychotics via modulating microglial superoxide generation have never been reported. Therefore, we herein investigated the effects of antipsychotics on the •O(2)(-) generation from phorbol-myristate-acetate (PMA)-stimulated rodent microglia by the electron spin resonance (ESR) spectroscopy and also examined the intracellular mechanism by intracellular Ca(2+) imaging and immunostaining. Neuronal damage induced by microglial activation was also investigated by the co-culture experiment. Among various antipsychotics, only aripiprazole inhibited the •O(2)(-) generation from PMA-stimulated microglia. Aripiprazole proved to inhibit the •O(2)(-) generation through the cascade of protein kinase C (PKC) activation, intracellular Ca(2+) regulation and NADPH oxidase activation via cytosolic p47(phox) translocation to the plasma/phagosomal membranes. Formation of neuritic beading, induced by PMA-stimulated microglia, was attenuated by pretreatment of aripiprazole. D2R antagonism has long been considered as the primary therapeutic action for schizophrenia. Aripiprazole with D2R partial agonism is effective like other antipsychotics with fewer side effects, while aripiprazole's therapeutic mechanism itself remains unclear. Our results imply that aripiprazole may have psychotropic effects by reducing the microglial oxidative reactions and following neuronal reactions, which puts forward a novel therapeutic hypothesis in schizophrenia research.

Microglia are intrinsic immune cells that release factors, including proinflammatory cytokines, nitric oxide (NO) and neurotrophins, following activation after disturbance in the brain. Elevation of intracellular Ca 2+ concentration ([Ca 2+ ]i) is important for microglial functions, such as the release of cytokines and NO from activated microglia. There is increasing evidence suggesting that pathophysiology of neuropsychiatric disorders is related to the inflammatory responses mediated by microglia. Brain-derived neurotrophic factor (BDNF) is a neurotrophin well known for its roles in the activation of microglia as well as in pathophysiology and/or treatment of neuropsychiatric disorders. We have recently reported that BDNF induces a sustained increase in [Ca 2+ ]i through binding with the truncated TrkB receptor, resulting in activation of the PLC pathway and store-operated calcium entry (SOCE) in rodent microglial cells. Sustained activation of SOCE, possibly mediated by TRP channels, occurred after brief BDNF application and contributed to the maintenance of sustained [Ca 2+ ]i elevation. Pretreatment with BDNF significantly suppressed the release of NO from activated microglia. Additionally, selective serotonin reuptake inhibitors (SSRIs), including paroxetine or sertraline, potentiated the BDNFinduced increase in [Ca 2+ ]i in rodent microglial cells This article provides a review of recent findings on the role of BDNF in the pathophysiology of neuropsychiatric disorders, especially by focusing on its effect on intracellular Ca 2+ signaling in microglial cells.

Microglia, which are a major glial component of the central nervous system (CNS), have recently been suggested to mediate neuroinflammation through the release of pro-inflammatory cytokines and nitric oxide (NO). Microglia are also known to play a critical role as resident immunocompetent and phagocytic cells in the CNS. Immunological dysfunction has recently been demonstrated to be associated with the pathophysiology of depression. However, to date there have only been a few studies on the relationship between microglia and depression. We therefore investigated if antidepressants can inhibit microglial activation in vitro. Our results showed that the selective serotonin reuptake inhibitors (SSRIs) paroxetine and sertraline significantly inhibited the generation of NO and tumor necrosis factor (TNF)-α from interferon (IFN)-γ-activated 6-3 microglia. We further investigated the intracellular signaling mechanism underlying NO and TNF-α release from IFN-γ-activated 6-3 microglia. Our results suggest that paroxetine and sertraline may inhibit microglial activation through inhibition of IFN-γ-induced elevation of intracellular Ca(2+). Our results suggest that the inhibitory effect of paroxetine and sertraline on microglial activation may not be a prerequisite for antidepressant function, but an additional beneficial effect.

Mood disorders have long and dominantly been regarded to be induced by disturbances of neuronal networks including synapses and neurotransmitters. Thus, the effects of psychotropic drugs including antidepressants have long been understood to modulate synaptic regulation via receptors and transporters of neurotransmitters such as serotonin. Recently, microglia, immune cells in the brain, have been indicated to have positive links to psychiatric disorders. Human imaging studies have shown microglial activation in the brain of patients with neuropsychiatric disorders such as depression and schizophrenia especially suicide victims. Animal models of psychiatric disorders including depression models have revealed the underlying microglial pathologies. In addition, various psychotropic drugs have been suggested to have direct effects on microglia. We herein introduce up-to-date knowledge of the effects of antidepressants on microglial modulation. In addition, we summarize recent findings of the interaction between microglia and neurotransmitters such as serotonin and melatonin. Finally, we propose the possibility that modulating microglia may be a key target in the treatment of various psychiatric disorders. Further translational investigations should be conducted to clarify this perspective, using rodent in vivo models, and novel translational research techniques such as directly induced microglia-like (iMG) cells from human peripheral blood.

The etiology of neuropsychiatric disorders such as autism spectrum disorders (ASDs) and schizophrenia remains unclear. However, many aspects of their neuropathology were recently reported to be closely associated with microglial dysfunction. Microglia, which are the major players of innate immunity in the central nervous system, respond rapidly to pathological changes, even minor ones, and contribute directly to neuroinflammation by producing various cytokines and free radicals. Recent studies revealed that microglia become activated over the course of ASDs and schizophrenia, using brain neuroimaging and postmortem analyzes. Recent studies have also shown inhibitory effects of some antipsychotics on the release of inflammatory cytokines and free radicals from activated microglia, causing synaptic and white matter abnormalities as seen in ASDs and schizophrenia postmortem brains. In addition, recent evidence strongly suggests a neurodevelopmental role for microglia in regulating the formation/function of neuronal circuits by their phagocytic activity and structural interactions with synapses. In Rett syndrome (RTT) particularly, microglia become dysfunctional and neurotoxic, thus contributing to abnormal brain development. Populating the brain of RTT mice with wild-type microglia was also found to arrest the disease, indicating an essential role of microglia in regulating the neurodevelopmental trajectory. In summary, emerging evidence indicates that microglia are closely related to the progression and outcome of ASDs and schizophrenia. Understanding microglial pathology may shed new light on the most promising therapeutic strategies for ASDs and schizophrenia, among other neuropsychiatric disorders.

Recent imaging studies have indicated that the pathophysiology of schizophrenia is closely related to white matter abnormalities and microglial activation. Additionally, recent clinical trials have suggested that atypical antipsychotics may have brain protective properties and that minocycline, an antibiotic with inhibitory effects on microglial activation, improves symptoms of schizophrenia. We have reported that not only atypical antipsychotics with dopamine D2 receptor (D2R) antagonism but also aripiprazole, a unique antipsychotic drug with D2R partial agonism, inhibit microglial activation in vitro. Thus, atypical antipsychotics may exert a beneficial influence on both microglia and oligodendrocytes, while the underlying mechanisms have not been clarified. Here, we investigated whether antipsychotics suppress oligodendrocyte damage by inhibiting microglial activation utilizing a co-culture model with microglia and oligodendrocytes. Pretreatment of aripiprazole and minocycline suppressed apoptosis of oligodendrocytes in the co-culture model with interferon-γ (IFN-γ)-activated microglia, while haloperidol, a traditional antipsychotic drug, did not. Aripiprazole and minocycline inhibited the production of tumor necrosis factor-alpha (TNF-α) from IFN-γ-activated microglia. Moreover, aripiprazole and minocycline attenuated the phosphorylation of signal transducer and activator of transcription 1 (STAT1) in microglia. Overall, our results suggest that aripiprazole and minocycline may have antipsychotic effects through reducing oligodendrocyte damage caused by microglial activation. These results put forward a novel therapeutic hypothesis in schizophrenia research. Future in vivo studies to confirm the present results should be performed.

A 1-2 min application of brain-derived neurotrophic factor (BDNF; 20 ng/ml) induced sustained elevation of intracellular Ca 2+ lasting > 90 min, using the fura-2 imaging of intracellular Ca 2+ mobilization, in visual cortical pyramidal neurons isolated from rats. BDNF increased intracellular Ca 2+ through the PLC-γ phosphorylation after theTrkB receptor tyrosine kinase activation. Either K252a or U73122 suppressed intracellular Ca 2+ in the absence of BDNF. We suggest that sustained activation of Trk B receptor tyrosine kinase and PLC-γ occurs after a brief BDNF application and contributes to the short-term maintenance (< 30 min) of the sustained intracellular Ca 2+ elevation.

Exposure to a stress task activates the sympathetic nervous system. Salivary 3-methoxy-4-hydroxy-phenylglycol (MHPG; the major metabolite of norepinephrine) concentrations closely reflect the plasma MHPG levels and are used as indices of noradrenergic activity. On the contrary, exposure to a stress task also activates the hypothalamic– pituitary–adrenal (HPA) axis resulting in the secretion of cortisol from the adrenal cortex. The level of salivary cortisol elevates in response to a stress task including oral presentations. We examined concentrations of salivary MHPG (sMHPG) and cortisol levels in a sample of doctors in training (6 males: mean age = 29.6 ± 3.0 years; 6 females: 26.8 ± 0.2 years) exposed to oral presentations. All the participants gave written informed consent, and this study was approved by the ethic committee of the Faculty of Medicine, Saga University. Each subject gave an oral presentation in a training course. In brief, each participant gave an oral presentation about the same theme: ‘‘How to treat patients who suffered from diabetes mellitus’’ to the audience who were invited. All the presentations were started in the afternoon at 2 p.m. and lasted for 1 h. After the presentation, the performance of each trainee was evaluated by the audience. Salivary sample was collected three times (just before the beginning of the presentation, immediately, and at 10 min after the presentation) for each participant. The concentration of sMHPG was measured by the gas chromatography-mass spectrometry. Salivary cortisol was measured using a commercially available enzyme immunoassay kit [1, 2]. The mean concentration of sMHPG did not change in both male (pre, 11.7 ± 2.1; post, 12.2 ± 1.3; 10 min, 11.7 ± 2.0 in ng/mL) and female (pre, 10.8 ± 1.7; post, 10.7 ± 2.1; 10 min, 10.5 ± 2.0) participants after the oral presentation. In contrast, the mean concentration of salivary cortisol was significantly increased in males (pre, 0.16 ± 0.03; post, 0.43 ± 0.09; 10 min, 0.31 ± 0.06 in lg/dL) but not in females (pre, 0.21 ± 0.05; post, 0.29 ± 0.07; 10 min, 0.24 ± 0.07) immediately and at 10 min after the oral presentation. Two-way analysis of variance with repeated measures revealed that the cortisol 9 sex interaction was significant (F = 5.64, P = 0.039). Male subjects are reported to show greater cortisol responses compared with females in response to public speaking. In contrast, female subjects show greater increase in cortisol levels in response to social rejection challenges [3]. Situations involving interpersonal concerns are perceived as more stressful for females, while the intellectual inferiority or failures of performance are perceived as more stressful for males. Our study supports recent findings suggesting that oral presentations might be more stressful for males. There are few reports on how stress tasks affect sMHPG and cortisol concentrations in a same population. Challenging behavioral tasks including simulated public speaking elevate sMHPG but not cortisol concentrations in volunteers who were injected with typhoid vaccine [4]. This suggests that a psychological stress could affect sMHPG but not cortisol concentrations. Our preliminary report suggests that a psychological stress could affect salivary cortisol but not MHPG concentrations. Y. Mizoguchi (&) A. Sakami Y. Imamura T. Tsuruta M. Egami S. Yamada Department of Neuropsychiatry, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan e-mail: ymizo@pk2.so-net.ne.jp

Microglia are intrinsic immune cells that release factors, including proinflammatory cytokines, NO, and neurotrophins, following activation after disturbance in the brain. Elevation of intracellular Ca2+ concentration ([Ca2+]i) is important for microglial functions, such as the release of cytokines and NO from activated microglia. There is increasing evidence suggesting that pathophysiology of neuropsychiatric disorders is related to the inflammatory responses mediated by microglia. Brain-derived neurotrophic factor (BDNF) is a neurotrophin well known for its roles in the activation of microglia as well as in pathophysiology and/or treatment of neuropsychiatric disorders. In this study, we observed that BDNF induced a sustained increase in [Ca2+]i through binding with the truncated tropomyosin-related kinase B receptor, resulting in activation of the PLC pathway and store-operated calcium entry in rodent microglial cells. RT-PCR and immunocytochemical techniques revealed that truncated tropomyosin-related kinase B-T1 receptors were highly expressed in rodent microglial cells. Sustained activation of store-operated calcium entry occurred after brief BDNF application and contributed to the maintenance of sustained [Ca2+]i elevation. Pretreatment with BDNF significantly suppressed the release of NO from activated microglia. Additionally, pretreatment of BDNF suppressed the IFN-γ-induced increase in [Ca2+]i, along with a rise in basal levels of [Ca2+]i in rodent microglial cells. We show direct evidence that rodent microglial cells are able to respond to BDNF, which may be important for the regulation of inflammatory responses, and may also be involved in the pathophysiology and/or the treatment of neuropsychiatric disorders.

Adolescent cannabis use is associated with an increased risk of schizophrenia and with impairments in cognitive processes reliant on the circuitry of the dorsolateral prefrontal cortex (DLPFC). Additionally, maternal cannabis use is associated with cognitive dysfunction in offspring. The effects of cannabis are mediated by the cannabinoid 1 receptor (CB1R), which is present in high density in the primate DLPFC. In order to determine how developmental changes in CB1Rs might render DLPFC circuitry vulnerable to cannabis exposure, we examined the density and innervation patterns of CB1R-immunoreactive (IR) axons and the expression of CB1R mRNA in the DLPFC from 81 macaque monkeys, ranging in age from embryonic 82 days to 18 years. Overall CB1R immunoreactivity in the gray matter robustly increased during the perinatal period and achieved adult levels by 1 week postnatal. However, laminar analyses revealed that CB1R-IR axon density significantly decreased with age in layers 1-2 but significantly increased in layer 4, especially during adolescence. In contrast, CB1R mRNA levels were highest 1 week postnatal, declined over the next 2 months, and then remained unchanged into adulthood. These findings provide a potential substrate for discrete, age-dependent effects of cannabis exposure on the maturation of primate DLPFC circuitry.

To study the influence of microglia on glutamatergic synaptic transmission in the acute phase of neuronal injury, we first examined the effects of primary cultured microglia transferred onto the organotypic cortical slice cultures. In these microglia-transferred cortical slice cultures, stimulation of the subcortical white matter induced fast excitatory postsynaptic potentials followed by N-methyl-D-aspartate (NMDA) receptor-mediated plateau-like potentials that were never observed in control slice cultures. A similar potentiation of NMDA receptor-mediated postsynaptic responses was also observed by an application of a microglial-conditioned medium (MCM, 10% v/v) in acute cortical slices. These effects of MCM disappeared after boiling or incubation with proteinase K. After fractionation of MCM by anion-exchange chromatography, the enhancing activity of each fraction was quantitated electrophysiologically. When each fraction was analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, the fraction 24 which showed the most potent enhancing activity on NMDA receptor-mediated responses contained a relatively strong protein band with a molecular mass of approximately 70 kDa. MCM also enhanced both glutamate- and NMDA-induced inward currents recorded from acutely isolated cortical neurons. It was also noted that glutamate and NMDA induced transient large inward currents during an application of MCM, which were never observed in the control condition. These observations strongly suggest that NMDA receptor-mediated responses can be potentiated by both heat- and protease-labile (presumably 70-kDa proteins) molecules released from microglia.

Psychiatric disorders have long and dominantly been regarded to be induced by disturbances of neuronal networks including synapses and neurotransmitters. Thus, the effects of psychotropic drugs such as antipsychotics and antidepressants have been understood to modulate synaptic regulation via receptors and transporters of neurotransmitters such as dopamine and serotonin. Recently, microglia, immunological/inflammatory cells in the brain, have been indicated to have positive links to psychiatric disorders. Positron emission tomography (PET) imaging and postmortem studies have revealed microglial activation in the brain of neuropsychiatric disorders such as schizophrenia, depression and autism. Animal models of neuropsychiatric disorders have revealed the underlying microglial pathologies. In addition, various psychotropic drugs have been suggested to have direct effects on microglia. Until now, the relationship between microglia, neurotransmitters and psychiatric disorders has not been well understood. Therefore, in this review, at first, we summarize recent findings of interaction between microglia and neurotransmitters such as dopamine, serotonin, norepinephrine, acetylcholine and glutamate. Next, we introduce up-to-date knowledge of the effects of psychotropic drugs such as antipsychotics, antidepressants and antiepileptics on microglial modulation. Finally, we propose the possibility that modulating microglia may be a key target in the treatment of various psychiatric disorders. Further investigations and clinical trials should be conducted to clarify this perspective, using animal in vivo studies and imaging studies with human subjects.