Faculty Profiles - ALEKSIC Branko

Papers - ALEKSIC Branko

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Relation Between Perinatal Depressive Symptoms, Harm Avoidance, and a History of Major Depressive Disorder: A Cohort Study of Pregnant Women in Japan. Reviewed International journal

Chika Kubota, Toshiya Inada, Tomoko Shiino, Masahiko Ando, Branko Aleksic, Aya Yamauchi, Maya Sato, Masako Ohara, Satomi Murase, Mako Morikawa, Yukako Nakamura, Takashi Okada, Setsuko Goto, Atsuko Kanai, Norio Ozaki

Frontiers in psychiatry Vol. 10 page： 515 - 515 2019.7

Publishing type：Research paper (scientific journal)

Introduction: The relationship between perinatal depressive symptoms, harm avoidance (HA), and a history of major depressive disorder (MDD) was examined in a prospective cohort study. Methods: This study was conducted from May 1, 2011, to December 31, 2016. A history of MDD was evaluated using the Inventory to Diagnose Depression, Lifetime version during pregnancy. Depressive state and HA were evaluated during pregnancy and at 1 month postnatal using the Edinburgh Postnatal Depression Scale (EPDS) and Temperament and Character Inventory, respectively. The relationship between these variances was examined using structural equation modeling. Results: A total of 338 participants with complete data were included in the present study. Pregnant women with compared with those without a history of MDD were observed to have a significantly higher intensity of HA and more severe depressive symptoms in both the prenatal and postnatal periods. A history of MDD affected the severity of depressive symptoms [standardized path coefficient (SPC) = 0.25, p < 0.001] and the intensity of HA during pregnancy (SPC = 0.36, p < 0.001). The intensity of HA during pregnancy affected that at 1 month postnatal (SPC = 0.78, p < 0.001), while the severity of depressive symptoms as assessed by the EPDS during pregnancy affected that at 1 month postnatal (SPC = 0.41, p < 0.001). The SPC for perinatal HA to postnatal depressive symptoms (SPC = 0.13, p = 0.014) was significant and higher than that for perinatal depressive symptoms to postnatal HA (SPC = 0.06, p = 0.087). Conclusion: The present results suggest that early intervention in pregnant women with a history of MDD or a high intensity of HA is important to prevent postnatal depressive symptoms.

DOI： 10.3389/fpsyt.2019.00515

Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect. Reviewed International journal

Masashi Ikeda, Atsushi Takahashi, Yoichiro Kamatani, Yukihide Momozawa, Takeo Saito, Kenji Kondo, Ayu Shimasaki, Kohei Kawase, Takaya Sakusabe, Yoshimi Iwayama, Tomoko Toyota, Tomoyasu Wakuda, Mitsuru Kikuchi, Nobuhisa Kanahara, Hidenaga Yamamori, Yuka Yasuda, Yuichiro Watanabe, Satoshi Hoya, Branko Aleksic, Itaru Kushima, Heii Arai, Manabu Takaki, Kotaro Hattori, Hiroshi Kunugi, Yuko Okahisa, Tohru Ohnuma, Norio Ozaki, Toshiyuki Someya, Ryota Hashimoto, Takeo Yoshikawa, Michiaki Kubo, Nakao Iwata

Schizophrenia bulletin Vol. 45 ( 4 ) page： 824 - 834 2019.7

Publishing type：Research paper (scientific journal)

Genome-wide association studies (GWASs) have identified >100 susceptibility loci for schizophrenia (SCZ) and demonstrated that SCZ is a polygenic disorder determined by numerous genetic variants but with small effect size. We conducted a GWAS in the Japanese (JPN) population (a) to detect novel SCZ-susceptibility genes and (b) to examine the shared genetic risk of SCZ across (East Asian [EAS] and European [EUR]) populations and/or that of trans-diseases (SCZ, bipolar disorder [BD], and major depressive disorder [MDD]) within EAS and between EAS and EUR (trans-diseases/populations). Among the discovery GWAS subjects (JPN-SCZ GWAS: 1940 SCZ cases and 7408 controls) and replication dataset (4071 SCZ cases and 54479 controls), both comprising JPN populations, 3 novel susceptibility loci for SCZ were identified: SPHKAP (Pbest = 4.1 × 10-10), SLC38A3 (Pbest = 5.7 × 10-10), and CABP1-ACADS (Pbest = 9.8 × 10-9). Subsequent meta-analysis between our samples and those of the Psychiatric GWAS Consortium (PGC; EUR samples) and another study detected 12 additional susceptibility loci. Polygenic risk score (PRS) prediction revealed a shared genetic risk of SCZ across populations (Pbest = 4.0 × 10-11) and between SCZ and BD in the JPN population (P ~ 10-40); however, a lower variance-explained was noted between JPN-SCZ GWAS and PGC-BD or MDD within/across populations. Genetic correlation analysis supported the PRS results; the genetic correlation between JPN-SCZ and PGC-SCZ was ρ = 0.58, whereas a similar/lower correlation was observed between the trans-diseases (JPN-SCZ vs JPN-BD/EAS-MDD, rg = 0.56/0.29) or trans-diseases/populations (JPN-SCZ vs PGC-BD/MDD, ρ = 0.38/0.12). In conclusion, (a) Fifteen novel loci are possible susceptibility genes for SCZ and (b) SCZ "risk" effect is shared with other psychiatric disorders even across populations.

DOI： 10.1093/schbul/sby140

Methylation analysis for postpartum depression: a case control study. Reviewed International journal

Yukako Nakamura, Masahiro Nakatochi, Shohko Kunimoto, Takashi Okada, Branko Aleksic, Miho Toyama, Tomoko Shiino, Mako Morikawa, Aya Yamauchi, Akira Yoshimi, Yoko Furukawa-Hibi, Taku Nagai, Masako Ohara, Chika Kubota, Kiyofumi Yamada, Masahiko Ando, Norio Ozaki

BMC psychiatry Vol. 19 ( 1 ) page： 190 - 190 2019.6

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Postpartum depression (PPD) is a major depressive disorder that occurs after childbirth. Objective diagnostic and predictive methods for PPD are important for early detection and appropriate intervention. DNA methylation has been recognized as a potential biomarker for major depressive disorder. In this study, we used methylation analysis and peripheral blood to search for biomarkers that could to lead to the development a predictive method for PPD. METHODS: Study participants included 36 pregnant women (18 cases and 18 controls determined after childbirth). Genome-wide DNA methylation profiles were obtained by analysis with an Infinium Human Methylation 450BeadChip. The association of DNA methylation status at each DNA methylation site with PPD was assessed using linear regression analysis. We also conducted functional enrichment analysis of PPD using The Database for Annotation, Visualization and Integrated Discovery 6.8 to explore enriched functional-related gene groups for PPD. RESULTS: In the analysis with postpartum depressed state as an independent variable, the difference in methylation frequency between the postpartum non-depressed group and the postpartum depressed group was small, and sites with genome-wide significant differences were not confirmed. After analysis by The Database for Annotation, Visualization and Integrated Discovery 6.8, we revealed four gene ontology terms, including axon guidance, related to postpartum depression. CONCLUSIONS: These findings may help with the development of an objective predictive method for PPD.

DOI： 10.1186/s12888-019-2172-x

Effects of Snoezelen-Multisensory environment on CARS scale in adolescents and adults with autism spectrum disorder. Reviewed International journal

Neda Novakovic, Milica Pejovic Milovancevic, Slavica Djukic Dejanovic, Branko Aleksic

Research in developmental disabilities Vol. 89 page： 51 - 58 2019.6

Publishing type：Research paper (scientific journal)

BACKGROUND: New classification system Diagnostic and statistical manual of mental disorders. 5th ed.(DSM - 5) includes sensory problems as one of the symptoms in diagnostic profile of Autism Spectrum Disorder (ASD). Researching the effects of sensory integration treatment may improve new approaches to the individuals with ASD. The objective of this study is to determine the effects of Snoezelen, multisensory environment on the severity of ASD and stereotyped/repetitive behaviours in adolescents and adults using CARS scale. METHOD: The study involved 40 subjects with ASD associated with intellectual difficulties of both sexes, aged 15-35. The subjects were randomly divided into two groups: a control one (without treatment) and an experimental one (with treatment). The assessments were rated by CARS (Childhood Autism Rating Scale) before and after the three-month treatment. RESULTS: In the experimental group, there was a statistically significant difference of the total CARS score before and after the treatment (p < 0.0005). Comparing the results of both experimental and control groups, a statistically significant difference was found on total CARS score (p < 0.0005). Conslusion: The results in the present study indicate that the continual sessions in Snoezelen room had effects on reducing severity of ASD and repetitive and stereotyped behaviours on CARS scale.

DOI： 10.1016/j.ridd.2019.03.007

Author Correction: Proteomic analysis of lymphoblastoid cell lines from schizophrenic patients. Reviewed International journal

Akira Yoshimi, Shinnosuke Yamada, Shohko Kunimoto, Branko Aleksic, Akihiro Hirakawa, Mitsuki Ohashi, Yurie Matsumoto, Kazuhiro Hada, Norimichi Itoh, Yuko Arioka, Hiroki Kimura, Itaru Kushima, Yukako Nakamura, Tomoko Shiino, Daisuke Mori, Satoshi Tanaka, Shuko Hamada, Yukihiro Noda, Taku Nagai, Kiyofumi Yamada, Norio Ozaki

Translational psychiatry Vol. 9 ( 1 ) page： 146 - 146 2019.5

Language：English Publishing type：Research paper (scientific journal)

The original Article required a few updates; one co-author name, which was given as Hiroki Kiumura, has been updated to Hiroki Kimura. Furthermore, supplementary information has been updated, and grant numbers have been added. These updates have been made to both the PDF and HTML versions of this Article.

DOI： 10.1038/s41398-019-0479-5

Joint Degree Program for Graduate Students at the Nagoya University Graduate School of Medicine. Reviewed

Hideki Kasuya, Branko Aleksic, Seiji Sumigama, Itzel Bustos, Hitoki Hasegawa, Mika P Kasai, Miho Kobayashi, Yumiko Samizo

Nagoya journal of medical science Vol. 81 ( 2 ) page： 183 - 192 2019.5

Publishing type：Research paper (scientific journal)

In a world of increasing academic mobility, most universities seek to give their students opportunities to experience education in different countries, which is especially true for senior research students. The Nagoya University Graduate School of Medicine started a joint degree program (JDP) for PhD students with the University of Adelaide, Faculty of Health Science (Australia) in 2015 and with Lund University Faculty of Medicine (Sweden) in 2017. Furthermore, we have started a new JDP with the University of Freiburg, Faculty of Medicine (Germany) in 2018. This article reports the issues specific to counterpart medical schools, including student's recruitment, the curriculum, and the general differences between each schools. JDPs are not only important for educational collaboration, but also as a strategy to encourage international research collaboration, which is a core criterion to a university's world-ranking reputation. Acquiring knowledge about educational strategies that are implemented in different foreign medical schools represents a unique opportunity to improve our own curriculum.

DOI： 10.18999/nagjms.81.2.183

Proteomic analysis of lymphoblastoid cell lines from schizophrenic patients. Reviewed International journal

Akira Yoshimi, Shinnosuke Yamada, Shohko Kunimoto, Branko Aleksic, Akihiro Hirakawa, Mitsuki Ohashi, Yurie Matsumoto, Kazuhiro Hada, Norimichi Itoh, Yuko Arioka, Hiroki Kimura, Itaru Kushima, Yukako Nakamura, Tomoko Shiino, Daisuke Mori, Satoshi Tanaka, Shuko Hamada, Yukihiro Noda, Taku Nagai, Kiyofumi Yamada, Norio Ozaki

Translational psychiatry Vol. 9 ( 1 ) page： 126 - 126 2019.4

Language：English Publishing type：Research paper (scientific journal)

Although a number of studies have identified several convincing candidate genes or molecules, the pathophysiology of schizophrenia (SCZ) has not been completely elucidated. Therapeutic optimization based on pathophysiology should be performed as early as possible to improve functional outcomes and prognosis; to detect useful biomarkers for SCZ, which reflect pathophysiology and can be utilized for timely diagnosis and effective therapy. To explore biomarkers for SCZ, we employed fluorescence two-dimensional differential gel electrophoresis (2D-DIGE) of lymphoblastoid cell lines (LCLs) (1st sample set: 30 SCZ and 30 CON). Differentially expressed proteins were sequenced by liquid chromatography tandem-mass spectrometry (LC-MS/MS) and identified proteins were confirmed by western blotting (WB) (1st and 2nd sample set: 60 SCZ and 60 CON). Multivariate logistic regression analysis was performed to identify an optimal combination of biomarkers to create a prediction model for SCZ. Twenty protein spots were differentially expressed between SCZ and CON in 2D-DIGE analysis and 22 unique proteins were identified by LC-MS/MS. Differential expression of eight of 22 proteins was confirmed by WB. Among the eight candidate proteins (HSPA4L, MX1, GLRX3, UROD, MAPRE1, TBCB, IGHM, and GART), we successfully constructed logistic regression models comprised of 4- and 6-markers with good discriminative ability between SCZ and CON. In both WB and gene expression analysis of LCL, MX1 showed reproducibly significant associations. Moreover, Mx1 and its related proinflamatory genes (Mx2, Il1b, and Tnf) were also up-regulated in poly I:C-treated mice. Differentially expressed proteins might be associated with molecular pathophysiology of SCZ, including dysregulation of immunological reactions and potentially provide diagnostic and prognostic biomarkers.

DOI： 10.1038/s41398-019-0461-2

A NOVEL RARE VARIANT R292H IN RTN4R AFFECTS GROWTH CONE FORMATION AND POSSIBLY CONTRIBUTES TO SCHIZOPHRENIA SUSCEPTIBILITY

Kimura Hiroki, Ishizuka Kanako, Wang Chenyao, Kushima Itaru, Morikawa Mako, Uno Yota, Okada Takashi, Inanda Toshiya, Aleksic Branko, Mori Daisuke, Ozaki Norio

EUROPEAN NEUROPSYCHOPHARMACOLOGY Vol. 29 page： S1014 - S1014 2019

INVESTIGATION OF NOVEL RARE VARIANTS IN NRXN1 CONTRIBUTES TO THE INCREASED RISK OF AUTISM SPECTRUM DISORDERS AND SCHIZOPHRENIA Reviewed International journal

Ishizuka Kanako, Aleksic Branko, Ozaki Norio

EUROPEAN NEUROPSYCHOPHARMACOLOGY Vol. 29 page： S829 - S829 2019

TARGET SEQUENCING OF GENES INVOLVED IN NEURODEVELOPMENT FROM WHOLE GENOME COPY NUMBER VARIATION ANALYSIS OF JAPANESE SCHIZOPHRENIA Reviewed International journal

Kimura Hiroki, Aleksic Branko, Ishizuka Kanako, Wang Chenyao, Kushima Itaru, Ozaki Norio

EUROPEAN NEUROPSYCHOPHARMACOLOGY Vol. 29 page： 1334 - 1334 2019

Stable factor structure of the Edinburgh Postnatal Depression Scale during the whole peripartum period: Results from a Japanese prospective cohort study. Reviewed International journal

Chika Kubota, Toshiya Inada, Yukako Nakamura, Tomoko Shiino, Masahiko Ando, Branko Aleksic, Aya Yamauchi, Mako Morikawa, Takashi Okada, Masako Ohara, Maya Sato, Satomi Murase, Setsuko Goto, Atsuko Kanai, Norio Ozaki

Scientific reports Vol. 8 ( 1 ) page： 17659 - 17659 2018.12

Language：English Publishing type：Research paper (scientific journal)

Early detection of perinatal depression is an urgent issue. Our study aimed to examine the construct validity and factor structure of the Japanese version of the Edinburgh Postnatal Depression Scale (EPDS) from a prospective cohort study from pregnancy to postpartum. A total of 1075 women completed all items of the EPDS at four time points: early pregnancy, late pregnancy, 5 days postpartum and 1 month postpartum. The participants were randomly divided into two sample sets. The first sample set (n = 304) was used for exploratory factor analysis, and the second sample set (n = 771) was used for confirmatory factor analysis. As a result, the Cronbach's alpha coefficients of the EPDS items were 0.762, 0.740, 0.765 and 0.772 at the four time points. From the confirmatory factor analysis of the EPDS in a sample set of Japanese women from pregnancy to postpartum, the following three factors were detected: depression (items 7, 9), anxiety (items 4, 5) and anhedonia (items 1, 2). In conclusion, the EPDS is a useful rating scale, and its factor structure is consistently stable during the whole peripartum period.

DOI： 10.1038/s41598-018-36101-z

Dysregulation of schizophrenia-related aquaporin 3 through disruption of paranode influences neuronal viability. Reviewed International journal

Kazuo Kunisawa, Takeshi Shimizu, Itaru Kushima, Branko Aleksic, Daisuke Mori, Yasuyuki Osanai, Kenta Kobayashi, Anna M Taylor, Manzoor A Bhat, Akiko Hayashi, Hiroko Baba, Norio Ozaki, Kazuhiro Ikenaka

Journal of neurochemistry Vol. 147 ( 3 ) page： 395 - 408 2018.11

Publishing type：Research paper (scientific journal)

Myelinated axons segregate the axonal membrane into four defined regions: the node of Ranvier, paranode, juxtaparanode, and internode. The paranodal junction consists of specific component proteins, such as neurofascin155 (NF155) on the glial side, and Caspr and Contactin on the axonal side. Although paranodal junctions are thought to play crucial roles in rapid saltatory conduction and nodal assembly, the role of their interaction with neurons is not fully understood. In a previous study, conditional NF155 knockout in oligodendrocytes led to disorganization of the paranodal junctions. To examine if disruption of paranodal junctions affects neuronal gene expression, we prepared total RNA from the retina of NF155 conditional knockout, and performed expression analysis. We found that the expression level of 433 genes changed in response to paranodal junction ablation. Interestingly, expression of aquaporin 3 (AQP3) was significantly reduced in NF155 conditional knockout mice, but not in cerebroside sulfotransferase knockout (CST-KO) mice, whose paranodes are not originally formed during development. Copy number variations have an important role in the etiology of schizophrenia (SCZ). We observed rare duplications of AQP3 in SCZ patients, suggesting a correlation between abnormal AQP3 expression and SCZ. To determine if AQP3 over-expression in NF155 conditional knockout mice influences neuronal function, we performed adeno-associated virus (AAV)-mediated over-expression of AQP3 in the motor cortex of mice and found a significant increase in caspase 3-dependent neuronal apoptosis in AQP3-transduced cells. This study may provide new insights into therapeutic approaches for SCZ by regulating AQP3 expression, which is associated with paranodal disruption.

DOI： 10.1111/jnc.14553

Assessment of a glyoxalase I frameshift variant, p.P122fs, in Japanese patients with schizophrenia. Reviewed International journal

Kanako Ishizuka, Hiroki Kimura, Itaru Kushima, Toshiya Inada, Yuko Okahisa, Masashi Ikeda, Nakao Iwata, Daisuke Mori, Branko Aleksic, Norio Ozaki

Psychiatric genetics Vol. 28 ( 5 ) page： 90 - 93 2018.10

Publishing type：Research paper (scientific journal)

Enhanced carbonyl stress has been observed in a subgroup of patients with schizophrenia. Glyoxalase I, which is encoded by GLO1, is an enzyme that protects against carbonyl stress. In this study, we focused on the association between rare genetic variants of GLO1 and schizophrenia. First, we identified one heterozygous frameshift variant, p.P122fs, in 370 Japanese schizophrenia cases with allele frequencies of up to 1% by exon-targeted mutation screening of GLO1. We then performed an association analysis on 1282 cases and 1764 controls with this variant. The variant was found in three cases and eight controls. There was no statistically significant association between p.P122fs in GLO1 and schizophrenia (P=0.25). This frameshift variant in GLO1 might occur at near-polymorphic frequencies in the Japanese population, although further investigations using larger samples and biological analyses are needed to exclude the possibility of a low-penetrance genetic risk associated with this variant.

DOI： 10.1097/YPG.0000000000000204

Impact of perceived rearing and social support on bonding failure and depression among mothers: A longitudinal study of pregnant women. Reviewed International journal

Masako Ohara, Masahiro Nakatochi, Takashi Okada, Branko Aleksic, Yukako Nakamura, Tomoko Shiino, Aya Yamauchi, Chika Kubota, Mako Morikawa, Satomi Murase, Setsuko Goto, Atsuko Kanai, Ryuji Kato, Masahiko Ando, Norio Ozaki

Journal of psychiatric research Vol. 105 page： 71 - 77 2018.10

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Although previous studies have reported associations between bonding failure, depression, social support among mothers, and perceived rearing, the causal relationships remain unclear. METHODS: A total of 855 women (mean age, 32.4 ± 4.4 years) completed the Mother-Infant Bonding Questionnaire (MIBQ), the Edinburgh Postnatal Depression Scale (EPDS), the Japanese version of the Social Support Questionnaire, and the Parental Bonding Instrument in early pregnancy before week 25 (T1) and at 1 month after delivery (T2). We created a path model to clarify the causal relationships between perinatal bonding failure, depression, social support, and perceived rearing during pregnancy and at 1 month after delivery. The model was tested using structural equation modeling. RESULTS: Our recursive model showed acceptable fit (chi-squared statistic/degree of freedom = 2.1, comparative fit index = 0.98, root mean square error of approximation = 0.04). It was revealed that: (1) at T1, higher overprotection significantly predicted MIBQ scores; (2) at T1, poorer social support significantly predicted both MIBQ and EPDS scores; and (3) at T1, both MIBQ and EPDS scores significantly predicted respective scores at T2. CONCLUSIONS: These results showed that bonding failure in the postpartum period was significantly influenced by mothers' own perceived rearing and social support during pregnancy. In addition, depression in the postpartum period was strongly influenced by social support during pregnancy. These findings suggest that psychosocial interventions that focus on both mothers' recollections of their own upbringing and social support during pregnancy are effective for preventing bonding failure and depression in the postpartum period.

DOI： 10.1016/j.jpsychires.2018.09.001

The Current Status and Future Prospects of Oncolytic Viruses in Clinical Trials against Melanoma, Glioma, Pancreatic, and Breast Cancers. Reviewed International journal

Ibrahim Ragab Eissa, Itzel Bustos-Villalobos, Toru Ichinose, Shigeru Matsumura, Yoshinori Naoe, Noriyuki Miyajima, Daishi Morimoto, Nobuaki Mukoyama, Wu Zhiwen, Maki Tanaka, Hitoki Hasegawa, Seiji Sumigama, Branko Aleksic, Yasuhiro Kodera, Hideki Kasuya

Cancers Vol. 10 ( 10 ) 2018.10

Publishing type：Research paper (scientific journal)

Oncolytic viral therapy has been accepted as a standard immunotherapy since talimogene laherparepvec (T-VEC, Imlygic®) was approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for melanoma treatment in 2015. Various oncolytic viruses (OVs), such as HF10 (Canerpaturev-C-REV) and CVA21 (CAVATAK), are now actively being developed in phase II as monotherapies, or in combination with immune checkpoint inhibitors against melanoma. Moreover, in glioma, several OVs have clearly demonstrated both safety and a promising efficacy in the phase I clinical trials. Additionally, the safety of several OVs, such as pelareorep (Reolysin®), proved their safety and efficacy in combination with paclitaxel in breast cancer patients, but the outcomes of OVs as monotherapy against breast cancer have not provided a clear therapeutic strategy for OVs. The clinical trials of OVs against pancreatic cancer have not yet demonstrated efficacy as either monotherapy or as part of combination therapy. However, there are several oncolytic viruses that have successfully proved their efficacy in different preclinical models. In this review, we mainly focused on the oncolytic viruses that transitioned into clinical trials against melanoma, glioma, pancreatic, and breast cancers. Hence, we described the current status and future prospects of OVs clinical trials against melanoma, glioma, pancreatic, and breast cancers.

DOI： 10.3390/cancers10100356

Comparative Analyses of Copy-Number Variation in Autism Spectrum Disorder and Schizophrenia Reveal Etiological Overlap and Biological Insights. Reviewed International journal

Itaru Kushima, Branko Aleksic, Masahiro Nakatochi, Teppei Shimamura, Takashi Okada, Yota Uno, Mako Morikawa, Kanako Ishizuka, Tomoko Shiino, Hiroki Kimura, Yuko Arioka, Akira Yoshimi, Yuto Takasaki, Yanjie Yu, Yukako Nakamura, Maeri Yamamoto, Tetsuya Iidaka, Shuji Iritani, Toshiya Inada, Nanayo Ogawa, Emiko Shishido, Youta Torii, Naoko Kawano, Yutaka Omura, Toru Yoshikawa, Tokio Uchiyama, Toshimichi Yamamoto, Masashi Ikeda, Ryota Hashimoto, Hidenaga Yamamori, Yuka Yasuda, Toshiyuki Someya, Yuichiro Watanabe, Jun Egawa, Ayako Nunokawa, Masanari Itokawa, Makoto Arai, Mitsuhiro Miyashita, Akiko Kobori, Michio Suzuki, Tsutomu Takahashi, Masahide Usami, Masaki Kodaira, Kyota Watanabe, Tsukasa Sasaki, Hitoshi Kuwabara, Mamoru Tochigi, Fumichika Nishimura, Hidenori Yamasue, Yosuke Eriguchi, Seico Benner, Masaki Kojima, Walid Yassin, Toshio Munesue, Shigeru Yokoyama, Ryo Kimura, Yasuko Funabiki, Hirotaka Kosaka, Makoto Ishitobi, Tetsuro Ohmori, Shusuke Numata, Takeo Yoshikawa, Tomoko Toyota, Kazuhiro Yamakawa, Toshimitsu Suzuki, Yushi Inoue, Kentaro Nakaoka, Yu-Ichi Goto, Masumi Inagaki, Naoki Hashimoto, Ichiro Kusumi, Shuraku Son, Toshiya Murai, Tempei Ikegame, Naohiro Okada, Kiyoto Kasai, Shohko Kunimoto, Daisuke Mori, Nakao Iwata, Norio Ozaki

Cell reports Vol. 24 ( 11 ) page： 2838 - 2856 2018.9

Language：English Publishing type：Research paper (scientific journal)

Compelling evidence in Caucasian populations suggests a role for copy-number variations (CNVs) in autism spectrum disorder (ASD) and schizophrenia (SCZ). We analyzed 1,108 ASD cases, 2,458 SCZ cases, and 2,095 controls in a Japanese population and confirmed an increased burden of rare exonic CNVs in both disorders. Clinically significant (or pathogenic) CNVs, including those at 29 loci common to both disorders, were found in about 8% of ASD and SCZ cases, which was significantly higher than in controls. Phenotypic analysis revealed an association between clinically significant CNVs and intellectual disability. Gene set analysis showed significant overlap of biological pathways in both disorders including oxidative stress response, lipid metabolism/modification, and genomic integrity. Finally, based on bioinformatics analysis, we identified multiple disease-relevant genes in eight well-known ASD/SCZ-associated CNV loci (e.g., 22q11.2, 3q29). Our findings suggest an etiological overlap of ASD and SCZ and provide biological insights into these disorders.

DOI： 10.1016/j.celrep.2018.08.022

Aberrant functional connectivity between the thalamus and visual cortex is related to attentional impairment in schizophrenia

Yamamoto Maeri, Kushima Itaru, Suzuki Ryohei, Branko Aleksic, Kawano Naoko, Inada Toshiya, Iidaka Tetsuya, Ozaki Norio

PSYCHIATRY RESEARCH-NEUROIMAGING Vol. 278 page： 35 - 41 2018.8

Genetic and animal model analyses reveal the pathogenic role of a novel deletion of RELN in schizophrenia. Reviewed International journal

Akira Sobue, Itaru Kushima, Taku Nagai, Wei Shan, Takao Kohno, Branko Aleksic, Yuki Aoyama, Daisuke Mori, Yuko Arioka, Naoko Kawano, Maeri Yamamoto, Mitsuharu Hattori, Toshitaka Nabeshima, Kiyofumi Yamada, Norio Ozaki

Scientific reports Vol. 8 ( 1 ) page： 13046 - 13046 2018.8

Language：English Publishing type：Research paper (scientific journal)

Reelin protein (RELN), an extracellular matrix protein, plays multiple roles that range from embryonic neuronal migration to spine formation in the adult brain. Results from genetic studies have suggested that RELN is associated with the risk of psychiatric disorders, including schizophrenia (SCZ). We previously identified a novel exonic deletion of RELN in a patient with SCZ. High-resolution copy number variation analysis revealed that this deletion included exons 52 to 58, which truncated the RELN in a similar manner to the Reln Orleans mutation (Relnrl-Orl). We examined the clinical features of this patient and confirmed a decreased serum level of RELN. To elucidate the pathophysiological role of the exonic deletion of RELN in SCZ, we conducted behavioral and neurochemical analyses using heterozygous Relnrl-Orl/+ mice. These mice exhibited abnormalities in anxiety, social behavior, and motor learning; the deficits in motor learning were ameliorated by antipsychotics. Methamphetamine-induced hyperactivity and dopamine release were significantly reduced in the Relnrl-Orl/+ mice. In addition, the levels of GABAergic markers were decreased in the brain of these mice. Taken together, our results suggest that the exonic deletion of RELN plays a pathological role, implicating functional changes in the dopaminergic and GABAergic systems, in the pathophysiology of SCZ.

DOI： 10.1038/s41598-018-31390-w

Postpartum depression among women in Nagoya indirectly exposed to the Great East Japan Earthquake. Reviewed International journal

Chika Kubota, Takashi Okada, Mako Morikawa, Yukako Nakamura, Aya Yamauchi, Masahiko Ando, Tomoko Shiino, Masako Ohara, Satomi Murase, Setsuko Goto, Atsuko Kanai, Tomoko Masuda, Branko Aleksic, Norio Ozaki

Scientific reports Vol. 8 ( 1 ) page： 11624 - 11624 2018.8

Language：English Publishing type：Research paper (scientific journal)

This study aimed to assess the situation of postpartum depression and maternal bonding in Nagoya, a city distant from the epicenter of the Great East Japan Earthquake that occurred on March 11, 2011. Among the participants at 1 month after childbirth between March 11, 2010 and March 10, 2013 (n = 188), 152 fully responded to the Edinburgh Postnatal Depression Scale (EPDS) and Mother-Infant Bonding Questionnaire (MIBQ). They were divided into pre-quake (n = 58), and 0-6, 6-12, 12-18, and 18-24 months after the earthquake groups (n = 20, 26, 29, and 19, respectively). The rate of mothers who scored above the cutoff point for the EPDS increased from 12.1% in the pre-quake to 35.0% in the 0-6 months group (p = 0.022). The EPDS total and anxiety subscale scores (mean ± standard error) were also significantly different between the pre-quake and 0-6 months after the earthquake groups (4.45 ± 0.50 vs. 7.95 ± 1.47, p = 0.024; 2.16 ± 0.26 vs. 3.65 ± 0.57, p = 0.021, respectively). The EPDS total and anxiety scores were the highest for the 0-6 months group, followed by the 6-12, 12-18, 18-24 months groups (p = 0.019, p = 0.022). MIBQ scores did not differ between the pre-quake and 0-6 months groups. Depressive symptoms, mainly explained by anxiety, increased after the earthquake with no changes in maternal bonding.

DOI： 10.1038/s41598-018-30065-w

Single-cell trajectory analysis of human homogenous neurons carrying a rare RELN variant. Reviewed International journal

Yuko Arioka, Emiko Shishido, Hisako Kubo, Itaru Kushima, Akira Yoshimi, Hiroki Kimura, Kanako Ishizuka, Branko Aleksic, Takuji Maeda, Mitsuru Ishikawa, Naoko Kuzumaki, Hideyuki Okano, Daisuke Mori, Norio Ozaki

Translational psychiatry Vol. 8 ( 1 ) page： 129 - 129 2018.7

Language：English Publishing type：Research paper (scientific journal)

Reelin is a protein encoded by the RELN gene that controls neuronal migration in the developing brain. Human genetic studies suggest that rare RELN variants confer susceptibility to mental disorders such as schizophrenia. However, it remains unknown what effects rare RELN variants have on human neuronal cells. To this end, the analysis of human neuronal dynamics at the single-cell level is necessary. In this study, we generated human-induced pluripotent stem cells carrying a rare RELN variant (RELN-del) using targeted genome editing; cells were further differentiated into highly homogeneous dopaminergic neurons. Our results indicated that RELN-del triggered an impaired reelin signal and decreased the expression levels of genes relevant for cell movement in human neurons. Single-cell trajectory analysis revealed that control neurons possessed directional migration even in vitro, while RELN-del neurons demonstrated a wandering type of migration. We further confirmed these phenotypes in neurons derived from a patient carrying the congenital RELN-del. To our knowledge, this is the first report of the biological significance of a rare RELN variant in human neurons based on individual neuron dynamics. Collectively, our approach should be useful for studying reelin function and evaluating mental disorder susceptibility, focusing on individual human neuronal migration.

DOI： 10.1038/s41398-018-0177-8

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