title: Bipolar Disorder Associated microRNA, miR-1908-5p, Regulates the Expression of Genes Functioning in Neuronal Glutamatergic Synapses.
abstract: Bipolar disorder (BD), characterized by recurrent mood swings between depression and mania, is a highly heritable and devastating mental illness with poorly defined pathophysiology. Recent genome-wide molecular genetic studies have identified several protein-coding genes and microRNAs (miRNAs) significantly associated with BD. Notably, some of the proteins expressed from BD-associated genes function in neuronal synapses, suggesting that abnormalities in synaptic function could be one of the key pathogenic mechanisms of BD. In contrast, however, the role of BD-associated miRNAs in disease pathogenesis remains largely unknown, mainly because of a lack of understanding about their target mRNAs and pathways in neurons. To address this problem, in this study, we focused on a recently identified BD-associated but uncharacterized miRNA, miR-1908-5p. We identified and validated its novel target genes includingDLGAP4,GRIN1,STX1A,CLSTN1andGRM4, which all function in neuronal glutamatergic synapses. Moreover, bioinformatic analyses of human brain expression profiles revealed that the expression levels of miR-1908-5p and its synaptic target genes show an inverse-correlation in many brain regions. In our preliminary experiments, the expression of miR-1908-5p was increased after chronic treatment with valproate but not lithium in control human neural progenitor cells. In contrast, it was decreased by valproate in neural progenitor cells derived from dermal fibroblasts of a BD subject. Together, our results provide new insights into the potential role of miR-1908-5p in the pathogenesis of BD and also propose a hypothesis that neuronal synapses could be a key converging pathway of some BD-associated protein-coding genes and miRNAs.
authors.affiliation: Department of Neuroscience and Division of Brain Korea 21 Biomedical Science, Korea University College of Medicine, Seoul 02841, Korea.
authors.forename: Yoonhee
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Neuroscience and Division of Brain Korea 21 Biomedical Science, Korea University College of Medicine, Seoul 02841, Korea.
authors.forename: Yinhua
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston 77030, USA.; Department of Pediatrics, Computational and Integrative Biomedical Research Center, Baylor College of Medicine, Houston 77030, USA.
authors.forename: Kaifang
authors.initials: K
authors.lastname: Pang
authors.affiliation: HPC-enabled Convergence Technology Research Division, Korea Institute of Science and Technology Information, Daejeon 34141, Korea.
authors.forename: Hyojin
authors.initials: H
authors.lastname: Kang
authors.affiliation: Department of Biomedical Sciences, Korea University College of Medicine, Seoul 02841, Korea.
authors.forename: Heejoo
authors.initials: H
authors.lastname: Park
authors.affiliation: Department of Neuroscience and Division of Brain Korea 21 Biomedical Science, Korea University College of Medicine, Seoul 02841, Korea.
authors.forename: Yeunkum
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Neuroscience and Division of Brain Korea 21 Biomedical Science, Korea University College of Medicine, Seoul 02841, Korea.
authors.forename: Bokyoung
authors.initials: B
authors.lastname: Lee
authors.affiliation: Department of Psychiatry, Korea University College of Medicine, Seoul 02841, Korea.
authors.forename: Heon-Jeong
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Neuroscience and Division of Brain Korea 21 Biomedical Science, Korea University College of Medicine, Seoul 02841, Korea.
authors.forename: Won-Ki
authors.initials: WK
authors.lastname: Kim
authors.affiliation: Department of Biomedical Sciences, Korea University College of Medicine, Seoul 02841, Korea.
authors.forename: Dongho
authors.initials: D
authors.lastname: Geum
authors.affiliation: Department of Neuroscience and Division of Brain Korea 21 Biomedical Science, Korea University College of Medicine, Seoul 02841, Korea.
authors.forename: Kihoon
authors.initials: K
authors.lastname: Han
keywords: Bipolar disorder; glutamatergic synapse; miR-1908-5p; microRNA