Kazuhiko Yamamuro

Potential primary roles of glial cells in the mechanisms of psychiatric disorders

While neurons have long been considered the major player in multiple brain functions such as perception, emotion, and memory, glial cells have been relegated to a far lesser position, acting as merely a “glue” to support neurons. Multiple lines of recent evidence, however, have revealed that glial cells such as oligodendrocytes, astrocytes, and microglia, substantially impact on neuronal function and activities and are significantly involved in the underlying pathobiology of psychiatric disorders. Indeed, a growing body of evidence indicates that glial cells interact extensively with neurons both chemically (e.g., through neurotransmitters, neurotrophic factors, and cytokines) and physically (e.g., through gap junctions), supporting a role for these cells as likely significant modifiers not only of neural function in brain development but also disease pathobiology. Since questions have lingered as to whether glial dysfunction plays a primary role in the biology of neuropsychiatric disorders or a role related solely to their support of neuronal physiology in these diseases, informative and predictive animal models have been developed over the last decade. In this article, we review recent findings uncovered using glia-specific genetically modified mice with which we can evaluate both the causation of glia dysfunction and its potential role in neuropsychiatric disorders such as autism and schizophrenia.

Differential patterns of blood oxygenation in the prefrontal cortex between patients with methamphetamine-induced psychosis and schizophrenia

Despite some slight differences in symptomatology, differential diagnosis of methamphetamine-induced psychosis (MAP) versus schizophrenia can be challenging because both disorders present a large overlap in their clinical symptoms. However, a recent study has shown that near-infrared spectroscopy (NIRS) performed during a cognitive task can be a powerful tool to differentiate between these two disorders. Here, we evaluated verbal fluency task performance during NIRS in 15 patients diagnosed with MAP and 19 with schizophrenia matched for age and sex. We used prefrontal probes and a 24-channel NIRS machine to measure the relative concentrations of oxyhaemoglobin every 0.1 s during the task. For each patient, the neurocognitive function and clinical psychopathology were evaluated using the Positive and Negative Symptom Scale (PANSS), and the Brief Assessment of Cognition in Schizophrenia (BACS). Oxyhaemoglobin changes in the prefrontal cortex were significantly higher in the MAP group compared to those in the schizophrenia group, particularly in the right dorsolateral prefrontal cortex. In contrast, we found no significant difference in PANSS and BACS scores. Our findings suggest that NIRS measurement could be applied to differentiate patients with MAP from those with schizophrenia, even in cases where clinical symptoms are similar.

Social Isolation During the Critical Period Reduces Synaptic and Intrinsic Excitability of a Subtype of Pyramidal Cell in Mouse Prefrontal Cortex

Juvenile social experience is crucial for the functional development of forebrain regions, especially the prefrontal cortex (PFC). We previously reported that social isolation for 2 weeks after weaning induces prefrontal cortex dysfunction and hypomyelination. However, the effect of social isolation on physiological properties of PFC neuronal circuit remained unknown. Since hypomyelination due to isolation is prominent in deep-layer of medial PFC (mPFC), we focused on 2 types of Layer-5 pyramidal cells in the mPFC: prominent h-current (PH) cells and nonprominent h-current (non-PH) cells. We found that a 2-week social isolation after weaning leads to a specific deterioration in action potential properties and reduction in excitatory synaptic inputs in PH cells. The effects of social isolation on PH cells, which involve reduction in functional glutamatergic synapses and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/N-methyl-d-aspartate charge ratio, are specific to the 2 weeks after weaning and to the mPFC. We conclude that juvenile social experience plays crucial roles in the functional development in a subtype of Layer-5 pyramidal cells in the mPFC. Since these neurons project to subcortical structures, a deficit in social experience during the critical period may result in immature neural circuitry between mPFC and subcortical targets.

Event-related potentials in drug-naïve pediatric patients with obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is one of the most common mental health disorders, characterized by obsessive thoughts and/or compulsive behaviors, which may involve specific disorders in cognition and/or information processing. Event-related potentials (ERPs) are commonly used as physiological measures of cognitive function as they are easily measured and noninvasive. In the present study, 20 drug-naïve pediatric patients with OCD were compared with 20 healthy control participants who were age- and sex-matched to perform the ERP. Based on the guidelines for evoked potential measurement, the P300 and mismatch negativity (MMN) were obtained by auditory odd-ball tasks. We found that the amplitudes of the P300 components in the Fz, Cz, Pz, C3, and C4 regions were significantly smaller in the OCD group compared with the control group. There were no between-group differences in P300 latency, MMN amplitude, or MMN latency. Moreover, we found significant correlations between scores on the Childrens Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) and P300 amplitudes at Cz, Pz, and C3. The present study is the first to report smaller P300s and the associations between P300 abnormalities and CY-BOCS scores.

Microglia-derived neuregulin expression in psychiatric disorders

Several studies have revealed that neuregulins (NRGs) are involved in brain function and psychiatric disorders. While NRGs have been regarded as neuron- or astrocyte-derived molecules, our research has revealed that microglia also express NRGs, levels of which are markedly increased in activated microglia. Previous studies have indicated that microglia are activated in the brains of individuals with autism spectrum disorder (ASD). Therefore, we investigated microglial NRG mRNA expression in multiple lines of mice considered models of ASD. Intriguingly, microglial NRG expression significantly increased in BTBR and socially-isolated mice, while maternal immune activation (MIA) mice exhibited identical NRG expression to controls. Furthermore, we observed a positive correlation between NRG expression in microglia and peripheral blood mononuclear cells (PBMCs) in mice, suggesting that NRG expression in human PBMCs may mirror microglia-derived NRG expression in the human brain. To translate these findings for application in clinical psychiatry, we measured levels of NRG1 splice-variant expression in clinically available PBMCs of patients with ASD. Levels of NRG1 type III expression in PBMCs were positively correlated with impairments in social interaction in children with ASD (as assessed using the Autistic Diagnostic Interview-Revised test: ADI-R). These findings suggest that immune cell-derived NRGs may be implicated in the pathobiology of psychiatric disorders such as ASD.

Event-related potentials reflect the efficacy of pharmaceutical treatments in children and adolescents with attention deficit/hyperactivity disorder.

Few objective biological measures of pharmacological treatment efficacy exist for attention deficit/hyperactivity disorder (ADHD). Although we have previously demonstrated that event-related potentials (ERPs) reflect the effects of osmotic-release methylphenidate in treatment of naïve pediatric patients with ADHD, whether this is true for the therapeutic effects of atomoxetine (ATX) is unknown. Here, we used the Japanese version of the ADHD rating-scale IV to evaluate 14 patients with ADHD, and compared their ERP data with 14 age- and sex-matched controls. We measured P300 and mismatch negativity (MMN) components during an auditory oddball task before treatment (treatment naïve) and after 2 months of ATX treatment. Compared with controls, P300 components at baseline were attenuated and prolonged in the ADHD group at Fz (fronto-central), Cz (centro-parietal), Pz (parietal regions), C3 and C4 electrodes. ATX treatment reduced ADHD symptomology, and after 2 months of treatment, P300 latencies at Fz, Cz, Pz, C3, and C4 electrodes were significantly shorter than those at baseline. Moreover, MMN amplitudes at Cz and C3 electrodes were significantly greater than those at baseline. Thus, ERPs may be useful for evaluating the pharmacological effects of ATX in pediatric and adolescent patients with ADHD.

Comparison of pervasive developmental disorder and schizophrenia by the Japanese version of the National Adult Reading Test

Abstract Objective. In adults, it is sometimes difficult to discriminate between pervasive developmental disorder (PDD) and schizophrenia (SCH) when positive symptoms are not outstanding. We examined whether the Japanese version of the National Adult Reading Test (JART), is a valid scale for evaluating pre-morbid intelligence quotient (IQ) in patients with SCH, and the Wechsler Adult Intelligence Scale-Revised (WAIS-R) are useful for helping to discriminate between PDD and SCH. Methods. Sixteen patients with adult PDD and 16 age-, education- and sex-matched patients with SCH participated in the present study. In addition, two groups were matched for JART and GAF scores. All subjects were scored on the JART and WAIS-R after informed consent on the aim of this study. Examiners who were blind to the diagnoses measured JART and WAIS-R. Results. Significant diagnosis-by-IQ examination interactions were found (F[1,30] = 10.049, P = 0.003). Furthermore, WAIS-R scores of the PDD group were higher than those of the SCH group (P = 0.002) considering two groups were matched for JART. Conclusions. The comparison of IQ in the PDD group and in the SCH group by JART and WAIS-R might be an easy and useful method for helping to discriminate between PDD and SCH.

Reduced Prefrontal Cortex Hemodynamic Response in Adults with Methamphetamine Induced Psychosis: Relevance for Impulsivity.

Patients with methamphetamine abuse/dependence often exhibit high levels of impulsivity, which may be associated with the structural abnormalities and functional hypoactivities observed in the frontal cortex of these subjects. Although near-infrared spectroscopy (NIRS) is a simple and non-invasive method for characterizing the clinical features of various psychiatric illnesses, few studies have used NIRS to directly investigate the association between prefrontal cortical activity and inhibitory control in patients with methamphetamine-induced psychosis (MAP). Using a 24-channel NIRS system, we compared hemodynamic responses during the Stroop color-word task in 14 patients with MAP and 21 healthy controls matched for age, sex and premorbid IQ. In addition, we used the Barrett Impulsivity Scale-11 (BIS-11) to assess impulsivity between subject groups. The MAP group exhibited significantly less activation in the anterior and frontopolar prefrontal cortex accompanied by lower Stroop color-word task performance, compared with controls. Moreover, BIS-11 scores were significantly higher in the MAP group, and were negatively correlated with the hemodynamic responses in prefrontal cortex. Our data suggest that reduced hemodynamic responses in the prefrontal cortex might reflect higher levels of impulsivity in patients with MAP, providing new insights into disrupted inhibitory control observed in MAP.

Tumor necrosis factor-alpha expression in peripheral blood mononuclear cells correlates with early childhood social interaction in autism spectrum disorder

ABSTRACT Autism spectrum disorder is a neurodevelopmental disorder characterized by impaired social interaction, poor communication skills, and repetitive/restrictive behaviors. Elevated blood levels of pro‐inflammatory cytokines have been reported in subjects with autism spectrum disorder. On the other hand, early childhood adverse experience also increases blood levels of these cytokines. Since social experience of children with autism spectrum disorder is generally unlike to typically developing children, we hypothesized that social interaction during childhood contribute to pro‐inflammatory cytokine expression in subjects with autism spectrum disorder. We compared revised Autism Diagnostic Interview scores and expression levels of pro‐inflammatory cytokines in peripheral blood mononuclear cells of subjects with autism spectrum disorder (n = 30). The score of domain A on the revised Autism Diagnostic Interview, indicating social interaction impairment in early childhood, was negatively correlated with tumor necrosis factor‐&agr; mRNA expression level in peripheral blood mononuclear cells but not interleukin‐1&bgr; or ‐6. Consistently, tumor necrosis factor‐&agr; mRNA expression was markedly low in subjects with autism spectrum disorder compared to typically developing children who presumably experienced the regular levels of social interaction. These findings suggest that the low blood levels of tumor necrosis factor‐&agr; mRNA in subjects with autism spectrum disorder might be due to impaired social interaction in early childhood. HighlightsTNF‐&agr; expression in PBMCs correlated with juvenile social interaction in ASD.TNF‐&agr; expression in PBMCs was lower in ASD than HDC.Juvenile social interaction‐dependent TNF‐&agr; expression might be associated with ASD.

Social isolation impairs remyelination in mice through modulation of IL-6

Recent studies have revealed that social experience affects myelination. These findings have important implications for disorders that feature abnormal myelination, such as multiple sclerosis (MS), as previous studies have shown that psychosocial stress exacerbates the pathobiology of MS. However, most studies have focused on psychosocial stress during the demyelination phase of MSand have not investigated the effects of social experience on remyelination. Thus, the current study sought to determine whether social experience can alter remyelination aftermyelindepletion. Myelininthemousemedialprefrontal cortexwasdepletedwithcuprizone, andthe effects of subsequent social isolation on remyelination were evaluated. Remyelination was severely impaired in socially isolatedmice. Social isolation also increased IL‐6 levels in themedialprefrontal cortex, and administrationof an IL‐6 inhibitor (ND50 = 0.01–0.03 μg for 0.25 ng/ml IL‐6) ameliorated remyelination impairments. Consistent with this result, IL‐6 administration (ED50 = 0.02–0.06 ng/ml) disturbed remyelination. In addition, neuron‐oligodendrocyte coculture experiments showed that IL‐6 treatment (ED50 ≤ 0.02 ng/ml) markedly impeded myelination, which was recoveredwith IL‐6 inhibitor administration (ND50 = 0.01–0.03 μg for 0.25 ng/ml IL‐6). This study provides the first direct evidence, to our knowledge, that social experience influences remyelination via modulation of IL‐6 expression. These findings indicate that psychosocial stress may disturb remyelination through regulation of IL‐6 expression in patients with such demyelinating diseases that involve remyelination asMS.—Makinodan, M., Ikawa, D., Miyamoto, Y., Yamauchi, J., Yamamuro, K., Yamashita, Y., Toritsuka, M., Kimoto, S., Okumura, K., Yamauchi, T., Fukami, S., Yoshino, H., Wanaka, A., Kishimoto, T. Social isolation impairs remyelination in mice through modulation of IL‐6. FASEB J. 30, 4267–4274 (2016). www.fasebj.org