Daisuke Ikawa

Increased L1 Retrotransposition in the Neuronal Genome in Schizophrenia

Recent studies indicate that long interspersed nuclear element-1 (L1) are mobilized in the genome of human neural progenitor cells and enhanced in Rett syndrome and ataxia telangiectasia. However, whether aberrant L1 retrotransposition occurs in mental disorders is unknown. Here, we report high L1 copy number in schizophrenia. Increased L1 was demonstrated in neurons from prefrontal cortex of patients and in induced pluripotent stem (iPS) cell-derived neurons containing 22q11 deletions. Whole-genome sequencing revealed brain-specific L1 insertion in patients localized preferentially to synapse- and schizophrenia-related genes. To study the mechanism of L1 transposition, we examined perinatal environmental risk factors for schizophrenia in animal models and observed an increased L1 copy number after immune activation by poly-I:C or epidermal growth factor. These findings suggest that hyperactive retrotransposition of L1 in neurons triggered by environmental and/or genetic risk factors may contribute to the susceptibility and pathophysiology of schizophrenia.

Gray and White Matter Changes in Subjective Cognitive Impairment, Amnestic Mild Cognitive Impairment and Alzheimer's Disease: A Voxel-Based Analysis Study

Subjective cognitive impairment may be a very early at-risk period of the continuum of dementia. However, it is difficult to discriminate at-risk states from normal aging. Thus, detection of the early pathological changes in the subjective cognitive impairment period is needed. To elucidate these changes, we employed diffusion tensor imaging and volumetry analysis, and compared subjective cognitive impairment with normal, mild cognitive impairment and Alzheimers disease. The subjects in this study were 39 Alzheimers disease, 43 mild cognitive impairment, 28 subjective cognitive impairment and 41 normal controls. There were no statistically significant differences between the normal control and subjective cognitive impairment groups in all measures. Alzheimers disease and mild cognitive impairment had the same extent of brain atrophy and diffusion changes. These results are consistent with the hypothetical model of the dynamic biomarkers of Alzheimers disease.

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.

Oligodendrocyte Plasticity with an Intact Cell Body In Vitro

Demyelination is generally regarded as a consequence of oligodendrocytic cell death. Oligodendrocyte processes that form myelin sheaths may, however, degenerate and regenerate independently of the cell body, in which case cell death does not necessarily occur. We provide here the first evidence of retraction and regeneration of oligodendrocyte processes with no cell death in vitro, using time-lapse imaging. When processes were severed mechanically in vitro, the cells did not undergo cell death and the processes regenerated in 36 h. In a separate experiment, moderate N-methyl-D-aspartate (NMDA) stimuli caused process retraction without apparent cell death, and the processes regained their elaborate morphology after NMDA was removed from the culture medium. These results strongly suggest that demyelination and remyelination can take place without concomitant cell death, at least in vitro. Process regeneration may therefore become a target for future therapy of demyelinating disorders.

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

Effects of the mode of re-socialization after juvenile social isolation on medial prefrontal cortex myelination and function

Social isolation is an important factor in the development of psychiatric disorders. It is necessary to develop an effective psychological treatment, such as cognitive rehabilitation, for children who have already suffered from social isolation, such as neglect and social rejection. We used socially isolated mice to validate whether elaborate re-socialization after juvenile social isolation can restore hypomyelination in the medial prefrontal cortex (mPFC) and the attendant functions manifested in socially isolated mice. While mice who underwent re-socialization with socially isolated mice after juvenile social isolation (Re-IS mice) demonstrated less mPFC activity during exposure to a strange mouse, as well as thinner myelin in the mPFC than controls, mice who underwent re-socialization with socially housed mice after juvenile social isolation (Re-SH mice) caught up with the controls in terms of most mPFC functions, as well as myelination. Moreover, social interaction of Re-IS mice was reduced as compared to controls, but Re-SH mice showed an amount of social interaction comparable to that of controls. These results suggest that the mode of re-socialization after juvenile social isolation has significant effects on myelination in the mPFC and the attendant functions in mice, indicating the importance of appropriate psychosocial intervention after social isolation.

Primary cerebral and cerebellar astrocytes display differential sensitivity to extracellular sodium with significant effects on apoptosis.

Central pontine myelinolysis is one of the idiopathic or iatrogenic brain dysfunction, and the most common cause is excessively rapid correction of chronic hyponatraemia. While myelin disruption is the main pathology, as the diagnostic name indicates, a previous study has reported that astrocyte death precedes the destruction of the myelin sheath after the rapid correction of chronic low Na+ levels, and interestingly, certain brain regions (cerebral cortex, hippocampus, etc.) are specifically damaged but not cerebellum. Here, using primary astrocyte cultures derived from rat cerebral cortex and cerebellum, we examined how extracellular Na+ alterations affect astrocyte death and whether the response is different between the two populations of astrocytes. Twice the amount of extracellular [Na+] and voltage‐gated Na+ channel opening induced substantial apoptosis in both populations of astrocytes, while, in contrast, one half [Na+] prevented apoptosis in cerebellar astrocytes, in which the Na+–Ca2+ exchanger, NCX2, was highly expressed but not in cerebral astrocytes. Strikingly, the rapid correction of chronic one half [Na+] exposure significantly increased apoptosis in cerebellar astrocytes but not in cerebral astrocytes. These results indicate that extracellular [Na+] affects astrocyte apoptosis, and the response to alterations in [Na+] is dependent on the brain region from which the astrocyte is derived. Copyright

Distinct patterns of blood oxygenation in the prefrontal cortex in clinical phenotypes of schizophrenia and bipolar disorder

BACKGROUND Schizophrenia (SZ) and bipolar disorder (BD) are characterized by different clinical symptoms, and have previously been considered as categorically separate. However, several lines of evidence controversially suggest that these two disorders may run on a continuum. While it is therefore important to evaluate the subtle differences between SZ and BD, few studies have investigated the difference of brain functioning between the two by focusing on the common symptoms of cognitive functioning and impulsivity, rather than positive/negative and mood symptoms. Recent developments in near-infrared spectroscopy (NIRS) technology have enabled noninvasive assessment of brain function in people with psychiatric disorders. METHODS Near-infrared spectroscopy (NIRS) using 24-channels was conducted during the verbal fluency task (VFT) and Stroop color-word task (SCWT) in 38 patients diagnosed with SZ, 34 patients with BD, and 26 age- and sex-matched healthy controls. RESULTS Oxyhemoglobin changes in the prefrontal cortex (PFC) were significantly lower particularly in the SZ compared to control group during the VFT. On the other hand, these were significantly lower particularly in the BD and SZ group to control group during the SCWT. Regression analysis showed that hemodynamic changes were significantly correlated with verbal memory and impulsivity in both disorders. CONCLUSION These findings suggest that different hemodynamic responses in the prefrontal cortex might reflect cognitive functioning and impulsivity, providing a greater insight into SZ and BD pathophysiology.

Altered gene expression in lymphoblastoid cell lines after subculture

Lymphoblastoid cell lines (LCLs) are nearly immortalized B lymphocytes that are used as long-lasting supply of human cells for studies on gene expression analyses. However, studies on the stability of the cellular features of LCLs are scarce. To address this issue, we measured gene expression in LCLs with different passage numbers and observed that gene expression substantially changed within 10 passages. In particular, the expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a well-known housekeeping gene, varied considerably during subculture; thus, the use GAPDH as an internal control may be unsuitable. In conclusion, this study highlights the need for exercising caution during determination of gene expression in LCLs.