Search

Background Antiepileptic drugs may cause delirium, and the risk may vary with each drug. However, related studies have provided inconsistent results. Aim To investigate whether antiepileptic drugs cause delirium by analysing adverse drug event reports compiled in the post-marketing stages of drugs and recorded in a database established by Japanese regulatory authorities. Method A total of 573,316 reports registered between 2004 and 2020 were used to create a dataset. The search terms for delirium as the item of interest were selected from the Standardized Medical Dictionary for Regulatory Activities Queries. Reporting odds ratios and 95% confidence intervals of adverse events associated with use of antiepileptic drugs were calculated after adjusting for potential confounders. Results There were 27,194 reports of antiepileptic drug-related adverse events. Of these, 189 reports were associated with antiepileptic drugs and delirium (crude reporting odds ratio, 1.66; 95% confidence interval, 1.43–1.92). The use of lacosamide (adjusted reporting odds ratio, 2.51; 95% confidence interval, 1.28–4.94), lamotrigine (adjusted reporting odds ratio, 1.71; 95% confidence interval, 1.16–2.52), levetiracetam (adjusted reporting odds ratio, 1.82; 95% confidence interval, 1.28–2.59), and valproic acid (adjusted reporting odds ratio, 1.53; 95% confidence interval, 1.19–1.97) was related to a significantly higher reporting odds ratio for delirium, even after adjustment for possible confounding factors. However, no signals for delirium were detected with any of these drugs under benzodiazepine receptor agonist usage. Conclusion The study findings suggest that antiepileptic drugs may cause delirium.

The beneficial effects of brain-derived neurotrophic factor (BDNF)—a member of the neurotrophin family—on cognitive function or dementia are well established in both rodents and human beings. In contrast, little is known about the association of proBDNF—a precursor protein with opposing neuronal effects of BDNF—with cognitive function in non-demented older adults. We analyzed brain magnetic resonance imaging findings of 256 community-dwelling older adults (mean age of 68.4 years). Serum BDNF and proBDNF levels were measured by quantitative enzyme-linked immunosorbent assay. Logistic regression analysis revealed that older age, less physical activity, hippocampal atrophy, and lower BDNF levels were independently associated with memory impairment determined by the Rivermead Behavioral Memory Test. Path analysis based on structural equation modeling indicated that age, sport activity, hippocampal atrophy and BDNF but not proBDNF were individually associated with Rivermead Behavioral Memory Test scores. These findings suggest that impaired BDNF function, in addition to physical inactivity and hippocampal atrophy, is associated with age-related memory impairment. Therefore, BDNF may be a potential target for dementia prevention.

The lifetime prevalence of depression is reported to be >10%, and it is an important illness that causes various disabilities over a long period of life. Neuroinflammation process is often reported to be closely linked to the pathophysiology of depression. Approximately one-third of depression is known to be treatment-resistant depression (TRD), in which the symptoms are refractory to adequate treatment. Cognitive dysfunction is one of the most important symptoms of depression that impedes the rehabilitation of patients with depression. Repetitive transcranial magnetic stimulation (rTMS) is a minimally invasive and effective treatment for TRD and is also known to be effective in cognitive dysfunction in depression. Since the details of the therapeutic mechanism of rTMS are still unknown, we have been conducting studies to clarify the therapeutic mechanism of rTMS, especially focusing on cognitive dysfunction in depression. In the present review, we present our latest results and discuss them from the standpoint of the neuroinflammation hypothesis of depression, while citing relevant literature.

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.

We herein report two cases with carbon monoxide- (CO-) induced delayed neuropsychiatric sequelae (DNS) successfully treated with hyperbaric oxygen therapy (HBOT) in attempt suicide by charcoal burning. The two patients with CO-induced DNS were successfully treated with a total of more than 100 sessions of HBOT. Frontal assessment battery (FAB) was useful to examine the effectiveness of HBOT objectively. In the future study, a large-randomized trial is required to establish the efficacy of HBOT for the treatment of DNS.

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.

BackgroundThis study aimed to investigate the association between serum levels of soluble triggering receptor expressed on myeloid cells 2 (sTREM2), a soluble form of an innate immune receptor expressed on the microglia, and brain volume in elderly people.MethodsThe 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 sTREM2 level measurements, brain MRI, Mini-Mental State Examination (MMSE), and Clinical Dementia Rating (CDR) were performed at Time 1 (2009–2011). Follow-up brain MRI, MMSE, and CDR were performed at Time 2 (2016–2017). The interval between Time 1 and Time 2 was approximately 7 years. Sixty-nine participants (16 men, mean age 72.69 ± 3.18 years; 53 women, mean age 72.68 ± 4.64 years) completed this study. We analyzed the correlation between serum sTREM2 levels (Time 1) and brain volume (Time 1, Time 2, and Time 1–Time 2 difference) using voxel-based morphometry implemented with Statistical Parametric Mapping.ResultsParticipants in this study had lower MMSE and CDR scores 7 years after the baseline evaluation. However, analyses at the cluster level by applying multiple comparison corrections (family wise error; P < 0.05) showed no correlation between serum sTREM2 levels and volume of different brain regions, either cross-sectional or longitudinal. ConclusionsSerum sTREM2 level could not serve as an immune biomarker of aging-related volume changes in brain regions closely related to cognitive function in elderly people aged 65 years and above.

The results of quantitative electroencephalography (qEEG) studies on electroconvulsive therapy (ECT) have been inconsistent, and indicators of the efficacy of ECT have not been clearly identified. In this study, we examined whether qEEG could be used as an indicator of the effect of ECT by measuring it during the course of treatment. We analyzed qEEG data before and after acute-phase ECT in 18 patients with schizophrenia, mood disorders, and other psychiatric disorders. We processed the qEEG data and compared the spectral power between the data acquired before and after ECT. The spectral power increased significantly after ECT in the delta, theta, and alpha bands. There was a strong significant correlation between the increase in the spectral power of the alpha band after acute ECT and improvement in the Brief Psychiatric Rating Scale score. Our results suggest that an increase in the alpha-band spectral power may be useful as an objective indicator of the treatment effect of acute ECT.

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 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.

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.

Background: Low-grade inflammation is implicated in the pathogenesis of small vessel disease of the brain. Furthermore, systemic inflammation has been associated with apathy. Because our previous study showed the association between deep white matter lesions (DWMLs) and apathy, we investigated the association between inflammation, DWMLs, and apathy. Methods: We analyzed the brain magnetic resonance imaging (MRI) findings in 259 community-dwelling adults (122 men and 137 women) with a mean age of 64.8 years. Serum concentrations of high-sensitivity C-reactive protein (CRP) were measured by a quantitative enzyme-linked immunosorbent assay with a sensitivity of 22 ng/L. Each item of the Starkstein apathy scale was quantified on a visual analogue scale. The association between silent brain lesions and CRP was tested using the forward stepwise method of logistic regression analysis. We used structural equation modeling (SEM) to test the contribution of inflammation and silent brain lesions to the apathetic behavior. Results: Although CRP level distribution was highly skewed (median: 0.589 mg/L, interquartile range: 0.292-1.326 mg/L), log-transformed CRP values (log10 CRP) were normally distributed. Medium to high tertiles of CRP were associated with metabolic syndrome. Logistic regression analysis revealed that log10 CRP (odds ratio [OR]: 2.90; 95% confidence interval [95%CI]: 1.25-6.71) was independently associated with confluent but not total DWMLs. Metabolic syndrome and age were also associated with confluent DWMLs. Path analysis based on SEM indicated that the direct path from log10 CRP to DWMLs was significant (β = 0.12, P = 0.039). The direct paths from metabolic syndrome to log10 CRP and to DWMLs were also significant. The direct path from DWMLs to apathy was significant (β = –0.17, P = 0.007) as was the direct path from education to apathy (β = 0.18, P = 0.003). However, the direct path from log10 CRP to apathy was not significant. The measures of model fitness showed that the presented model reasonably fit the data. Conclusions: Independent of common vascular risk factors, elevated serum CRP levels were associated with confluent DWMLs. Although DWMLs were associated with apathy, direct association between inflammation and apathy was not shown.

Chronic kidney disease (CKD) is a substantial public health problem. In the United States, almost 8% of the population has CKD and 571,000 patients receive treatment for endstage renal disease. Although the incidence of CKD is increasing in all age groups, this is particularly true in the elderly. There is a greater risk of developing neurocognitive disorders and dementia in older adults, and amajor determinant of quality of life in the elderly is the level of cognitive function. Recent data in this regard suggest that in individuals at all stages of CKD, theremay be a higher risk of developing dementia and cognitive impairment than in those without CKD. Given the increase in life expectancy and the aging of the population in industrialized countries, the neurocognitive disorder burden associated with CKD is expected to worsen. Up to 70% of patients undergoing hemodialysis who are 55 years and older have moderate to severe chronic cognitive impairment, yet it is largely undiagnosed. Dementia is associated with high risks of death, dialysis withdrawal, hospitalization, and disability among patients with endstage renal disease. We describe the case of Ms. A, who is undergoing hemodialysis, in whom various neuropsychiatric symptoms developed, and we review the relevant literature on neurocognitive disorders in CKD. University, Saga, Japan (HT, TH, JM, YH, YM, TK, AM); Department of Radiology, Faculty of Medicine, Saga University, Saga, Japan (TN); Department of Neuropsychiatry, Graduate School of Medical Sciences, Fukuoka, Japan (TAK). Send correspondence and reprint requests to Hiroshi Tateishi, M.D., and Akira Monji, M.D., Address: 5-1-1 Nabeshima, Saga, Japan; e-mail: muutoyukainanakamatachi@gmail.com, amonji@hf.rim.or.jp & 2016 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved. Case Report

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.

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.

Low-grade inflammation is implicated in the pathogenesis of atherosclerosis, metabolic syndrome, and apathy as a form of vascular depression. We analyzed the brain magnetic resonance imaging findings in 259 community-dwelling older adults (122 men and 137 women, with a mean age of 68.4 years). The serum concentrations of high-sensitivity C-reactive protein (hsCRP) were measured by a quantitative enzyme-linked immunosorbent assay. Logistic regression analysis revealed that the log10 hsCRP value and the presence of a metabolic syndrome were independently associated with confluent but not punctate deep white matter lesions (DWMLs). Path analysis based on structural equation modeling (SEM) indicated that the direct path from the log10 hsCRP to the DWMLs was significant (&beta, = 0.119, p = 0.039). The direct paths from the metabolic syndrome to the log10 hsCRP and to the DWMLs were also significant. The direct path from the DWMLs to apathy (&beta, = &minus, 0.165, p = 0.007) was significant, but the direct path from the log10 hsCRP to apathy was not significant. Inflammation (i.e., elevated serum hsCRP levels) was associated with DWMLs independent of common vascular risk factors, while DWMLs were associated with apathy. The present analysis with SEM revealed the more realistic scheme that low-grade inflammation was associated with apathy indirectly via DWMLs in community-dwelling older adults.

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.

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.

Brain-derived neurotrophic factor (BDNF) modulates several distinct aspects of synaptic transmission, including GABAergic transmission. Exposure to BDNF alters properties of GABA(A) receptors and induces changes in the expression level at the cell surface. Although phospholipase C-related inactive protein-1 (PRIP-1) plays an important role in GABA(A) receptor trafficking and function, its role in BDNF-dependent modulation of these receptors, together with the role of PRIP-2, was investigated using neurons cultured from PRIP double knock-out mice. The BDNF-dependent inhibition of whole cell GABA-evoked currents observed in wild type neurons was not detected in neurons cultured from knock-out mice. Instead, a gradual increase in GABA-evoked currents in these neurons correlated with a gradual increase in phosphorylation of GABA(A) receptor beta3 subunit in response to BDNF. To characterize the specific role(s) that PRIP plays as components of underlying molecular machinery, we examined the recruitment of protein phosphatase(s) to GABA(A) receptors. We demonstrate that PRIP associates with phosphatases as well as with beta subunits. PRIP was found to colocalize with GABA(A) receptor clusters in cultured neurons and with recombinant GABA(A) receptors when co-expressed in HEK293 cells. Importantly, a peptide mimicking a domain of PRIP involved in binding to beta subunits disrupted the co-localization of these proteins in HEK293 cells and potently inhibited the BDNF-mediated attenuation of GABA(A) receptor currents in wild type neurons. Together, the results suggest that PRIP plays an important role in BDNF-dependent regulation of GABA(A) receptors by mediating the specific association between beta subunits of these receptors with protein phosphatases.

A 69-year-old woman with no family history of mental or neurologic diseases or hypoxic episodes began to show gradual progressive apathy and difficulties in household work at about 50 years of age, followed by emotional blunting. At 68 years of age, she developed catatonia-like signs with little or no spontaneous movement, mutism, and refusal to eat or drink. Frontotemporal dementia (FTD) was suspected because of the bilateral frontal and temporal atrophy shown by an MRI study. At that time, her family found that her symptoms were temporarily resolved with zolpidem without sleepiness. Medical examinations, including a complete blood cell count, and liver, renal, and thyroid function tests, showed no abnormalities. EEG showed dominant α rhythm with occasional slow waves, without any evidence of disturbance of consciousness. Psychotropic agents including zopiclone, lorazepam, brotizolam, alprazolam, diazepam, quazepam, quetiapine, fluvoxamine, lamotrigine, mirtazapine, and amantadine did not resolve her catatonia-like signs. No psychological tests could be performed because of her catatonic state. About 30 minutes after the oral administration of zolpidem (5 mg), her catatonia-like signs gradually ameliorated, and the effect lasted for a few hours. Psychological tests following zolpidem administration demonstrated that her Mini-Mental State Examination score was 21/30, showing disturbances in orientation, attention, and calculation, while the Frontal Assessment Battery score was 11/18 with signs of perseveration that indicated the hypofunction of the frontal lobe. The Bush-Francis Catatonia Rating Scale score changed from 26 to 3 (table). Brain perfusion scans were performed before and after the administration of zolpidem (figure). In both scans, a severe perfusion decrease was observed in bilateral high-frontal lobes, and a mild decrease was observed in bilateral temporal lobes, which was compatible with FTD. After the oral administration of zolpidem, the perfusion was decreased in the brainstem and improved in the thalamus and some cortical areas, including the left parieto-temporal lobe and left cerebellar cortex. The anticatatonic effect of zolpidem has been observed for these 2 years without any side effect.

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.

The activation of the inflammatory/immunological response system is suggested to be related to the pathophysiology of schizophrenia. Aripiprazole is a novel atypical antipsychotic, which is a high-affinity dopamine D(2) receptor partial agonist. Atypical antipsychotics, all of which have dopamine D(2) receptor antagonism, have recently reported to have significantly inhibitory effects on interferon (IFN)-gamma-induced microglial activation in vitro. In the present study, we investigated whether or not aripiprazole also has anti-inflammatory effect on IFN-gamma-induced microglial activation. Not quinpirole, dopamine D(2) full agonist, but aripiprazole significantly inhibited the generation of nitric oxide (NO) and tumor necrosis factor (TNF)-alpha from IFN-gamma-activated microglia and suppressed the IFN-gamma-induced elevation of intracellular Ca(2+) concentrations ([Ca(2+)](i)) in murine microglial cells. Increased [Ca(2+)](i) has been reported to be required, but by itself not sufficient, for the release of NO and certain cytokines. As a result, we can speculate that aripiprazole may inhibit IFN-gamma-induced microglial activation through the suppression of IFN-gamma-induced elevation of [Ca(2+)](i) in microglia. Our results demonstrated that not only antipsychotics which have dopamine D(2) receptor antagonism but also aripiprazole have anti-inflammatory effects via the inhibition of microglial activation. Antipsychotics may therefore have a potentially useful therapeutic effect on patients with schizophrenia by reducing the microglial inflammatory reactions.

The number of postsynaptic gamma-aminobutyric acid type A (GABAA) receptors is a fundamental determinant of the variability of inhibitory synaptic responses in the central nervous system. In rat visual cortex, [3H]SR-95531 binding assays revealed that brain-derived neurotrophic factor (BDNF), one of the neurotrophins, induced a rapid increase in the total number of cell surface GABAA receptors, through the activation of Trk B receptor tyrosine kinases. We also demonstrated that BDNF rapidly induced a sustained potentiation of GABAA receptor-mediated currents, using nystatin-perforated patch clamp recordings, in visual cortical layer 5 pyramidal neurons freshly isolated from P14 rats. The potentiation was caused by the activation of Trk B receptor tyrosine kinase and phospholipase C-gamma. In addition, intracellular Ca2+ was important for the potentiation of GABAA responses induced by BDNF. The selective increase in mean miniature inhibitory postsynaptic (mIPSC) current amplitude without effects on mIPSC time courses supports the idea that BDNF rapidly induces an increase in the total number of cell surface functional GABAA receptors in visual cortical pyramidal neurons. These results suggest that BDNF could alter the number of cell surface GABAA receptors in a region-specific manner.

During the development of the hippocampus, the action of GABA shifts from depolarizing to hyperpolarizing, and brain-derived neurotrophic factor (BDNF) has important roles in GABAergic transmission. We demonstrate that BDNF (20 ng ml-1) rapidly and reversibly potentiates postsynaptic GABAA receptor-mediated currents (by 80.5 +/- 14.3 %, n = 10) in hippocampal CA1 pyramidal neurons isolated from postnatal day (P)6 rats, using nystatin-perforated patch-clamp recordings. This potentiation is caused by an elevation of intracellular Ca2+ that occurs in response to the activation of Trk B receptor tyrosine kinase and phospholipase C-gamma. The modulation of the GABAA responses by BDNF in hippocampal CA1 pyramidal neurons isolated from P10 rats was more diverse (from potentiating to inhibitory), and at P14, BDNF induced a long-lasting inhibition. In addition, Ca2+/calmodulin-dependent protein kinase 2 plays important roles in the potentiating, but not in the inhibitory effect, of BDNF on the GABAA responses. These results suggest that changes in the intracellular signalling pathway could contribute to the developmental shift of the actions of BDNF on inhibitory systems.

胸部食道癌切除術に際し, 右迷走神経肺枝と右気管支動脈を積極的にのこす呼吸機能温存手術を12例に行った.この術式を施行した症例は他の症例に比べ, 肺合併症や手術死亡が減少する傾向がみとめられるのみならず, いわゆる拡大リンパ節郭清例に再々みられる術後の著しい呼吸機能の低下を軽減する効果がみとめられた.しかも, この手術によって, 上縦隔, とくに気管分岐部周辺のリンパ節郭清が不十分になることもなく, 短期的ではあるが, 予後の差もみとめられなかった.したがって, 呼吸機能温存手術は, poor risk例のみならず, 拡大リンパ節郭清術や重要臓器合併切除術においても, 採用されるべき有用な術式と考えられる.