title: Microglia-derived neuregulin expression in psychiatric disorders.
abstract: 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.
authors.affiliation: Department of Psychiatry, Nara Medical University School of Medicine, Nara, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ikawa
authors.affiliation: Department of Psychiatry, Nara Medical University School of Medicine, Nara, Japan. Electronic address: mmm@naramed-u.ac.jp.
authors.forename: Manabu
authors.initials: M
authors.lastname: Makinodan
authors.affiliation: Research Center for Child Mental Development, University of Fukui, Japan; Department of Development of Functional Brain Activities, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Fukui, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Iwata
authors.affiliation: Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyusyu University, Fukuoka, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ohgidani
authors.affiliation: Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyusyu University, Fukuoka, Japan; Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Japan.
authors.forename: Takahiro A
authors.initials: TA
authors.lastname: Kato
authors.affiliation: Department of Psychiatry, Nara Medical University School of Medicine, Nara, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Yamashita
authors.affiliation: Department of Psychiatry, Nara Medical University School of Medicine, Nara, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamamuro
authors.affiliation: Department of Psychiatry, Nara Medical University School of Medicine, Nara, Japan.
authors.forename: Sohei
authors.initials: S
authors.lastname: Kimoto
authors.affiliation: Department of Psychiatry, Nara Medical University School of Medicine, Nara, Japan.
authors.forename: Michihiro
authors.initials: M
authors.lastname: Toritsuka
authors.affiliation: Department of Psychiatry, Nara Medical University School of Medicine, Nara, Japan.
authors.forename: Takahira
authors.initials: T
authors.lastname: Yamauchi
authors.affiliation: Department of Psychiatry, Nara Medical University School of Medicine, Nara, Japan.
authors.forename: Shin-Ichi
authors.initials: SI
authors.lastname: Fukami
authors.affiliation: Department of Psychiatry, Nara Medical University School of Medicine, Nara, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yoshino
authors.affiliation: Department of Psychiatry, Nara Medical University School of Medicine, Nara, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Okumura
authors.affiliation: Department of Anatomy and Neuroscience, Nara Medical University School of Medicine, Nara, Japan.
authors.forename: Tatsuhide
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Department of Anatomy and Neuroscience, Nara Medical University School of Medicine, Nara, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Wanaka
authors.affiliation: Department of Organ Anatomy, Graduate School of Medicine, Tohoku University, Sendai, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Owada
authors.affiliation: Faculty of Sociology, Chukyo University, Toyota, Japan.
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Tsujii
authors.affiliation: Aichi Children's Health and Medical Center, Obu, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Sugiyama
authors.affiliation: Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Tsuchiya
authors.affiliation: Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Suita, Osaka, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Mori
authors.affiliation: Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Suita, Osaka, Japan; Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Hashimoto
authors.affiliation: Research Center for Child Mental Development, University of Fukui, Japan; Department of Development of Functional Brain Activities, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Fukui, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Matsuzaki
authors.affiliation: Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyusyu University, Fukuoka, Japan.
authors.forename: Shigenobu
authors.initials: S
authors.lastname: Kanba
authors.affiliation: Department of Psychiatry, Nara Medical University School of Medicine, Nara, Japan.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Kishimoto
mesh_terms: D000293:Adolescent; D000818:Animals; D000067877:Autism Spectrum Disorder / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D002648:Child; D004195:Disease Models, Animal; D006801:Humans; D007398:Interpersonal Relations; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D051379:Mice; D017628:Microglia / Q000378:metabolism*; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D012934:Social Isolation
chemical_list: D020890:Neuregulin-1
keywords: Autism spectrum disorder; Cytokine; Microglia; Neuregulin; PBMCs