title: Regulation of Brain-Derived Neurotrophic Factor Exocytosis and Gamma-Aminobutyric Acidergic Interneuron Synapse by the Schizophrenia Susceptibility Gene Dysbindin-1.
abstract: Genetic variations in dystrobrevin binding protein 1 (DTNBP1 or dysbindin-1) have been implicated as risk factors in the pathogenesis of schizophrenia. The encoded protein dysbindin-1 functions in the regulation of synaptic activity and synapse development. Intriguingly, a loss of function mutation in Dtnbp1 in mice disrupted both glutamatergic and gamma-aminobutyric acidergic transmission in the cerebral cortex; pyramidal neurons displayed enhanced excitability due to reductions in inhibitory synaptic inputs. However, the mechanism by which reduced dysbindin-1 activity causes inhibitory synaptic deficits remains unknown.
  
  
  
  We investigated the role of dysbindin-1 in the exocytosis of brain-derived neurotrophic factor (BDNF) from cortical excitatory neurons, organotypic brain slices, and acute slices from dysbindin-1 mutant mice and determined how this change in BDNF exocytosis transsynaptically affected the number of inhibitory synapses formed on excitatory neurons via whole-cell recordings, immunohistochemistry, and live-cell imaging using total internal reflection fluorescence microscopy.
  
  
  
  A decrease in dysbindin-1 reduces the exocytosis of BDNF from cortical excitatory neurons, and this reduction in BDNF exocytosis transsynaptically resulted in reduced inhibitory synapse numbers formed on excitatory neurons. Furthermore, application of exogenous BDNF rescued the inhibitory synaptic deficits caused by the reduced dysbindin-1 level in both cultured cortical neurons and slice cultures.
  
  
  
  Taken together, our results demonstrate that these two genes linked to risk for schizophrenia (BDNF and dysbindin-1) function together to regulate interneuron development and cortical network activity. This evidence supports the investigation of the association between dysbindin-1 and BDNF in humans with schizophrenia.
authors.affiliation: Molecular Neurophysiology Laboratory, Signature Program in Neuroscience and Behavioral Disorders, Duke-National University of Singapore Graduate Medical School, Singapore, Singapore.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Yuan
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland.
authors.forename: Feng
authors.initials: F
authors.lastname: Yang
authors.affiliation: Molecular Neurophysiology Laboratory, Signature Program in Neuroscience and Behavioral Disorders, Duke-National University of Singapore Graduate Medical School, Singapore, Singapore.
authors.forename: Yixin
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Molecular Neurophysiology Laboratory, Signature Program in Neuroscience and Behavioral Disorders, Duke-National University of Singapore Graduate Medical School, Singapore, Singapore.
authors.forename: Shawn
authors.initials: S
authors.lastname: Tan
authors.affiliation: Molecular Neurophysiology Laboratory, Signature Program in Neuroscience and Behavioral Disorders, Duke-National University of Singapore Graduate Medical School, Singapore, Singapore.
authors.forename: Nilofer
authors.initials: N
authors.lastname: Husain
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland.
authors.forename: Ming
authors.initials: M
authors.lastname: Ren
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland.
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland.
authors.forename: Keri
authors.initials: K
authors.lastname: Martinowich
authors.affiliation: Molecular Neurophysiology Laboratory, Signature Program in Neuroscience and Behavioral Disorders, Duke-National University of Singapore Graduate Medical School, Singapore, Singapore.
authors.forename: Julia S
authors.initials: JS
authors.lastname: Ng
authors.affiliation: Molecular Neurophysiology Laboratory, Signature Program in Neuroscience and Behavioral Disorders, Duke-National University of Singapore Graduate Medical School, Singapore, Singapore.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Kim
authors.affiliation: Singapore Bioimaging Consortium, Singapore, Singapore.
authors.forename: Weiping
authors.initials: W
authors.lastname: Han
authors.affiliation: Institute for Developmental Research, Aichi Human Service Center, Kasugai, Japan.
authors.forename: Koh-Ichi
authors.initials: KI
authors.lastname: Nagata
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Weinberger
authors.affiliation: Molecular Neurophysiology Laboratory, Signature Program in Neuroscience and Behavioral Disorders, Duke-National University of Singapore Graduate Medical School, Singapore, Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. Electronic address: shawn.je@duke-nus.edu.sg.
authors.forename: H Shawn
authors.initials: HS
authors.lastname: Je
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism* / Q000494:pharmacology; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian; D005089:Exocytosis / Q000235:genetics*; D006801:Humans; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009924:Organ Culture Techniques; D011188:Potassium / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D013569:Synapses / Q000187:drug effects / Q000235:genetics; D055366:Synaptic Potentials / Q000187:drug effects / Q000235:genetics; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C432416:DTNBP1 protein, human; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D034741:RNA, Small Interfering; C118623:Slc32a1 protein, rat; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; D005680:gamma-Aminobutyric Acid; D011188:Potassium
keywords: Brain-derived neurotrophic factor (BDNF); DTNBP1; Dysbindin-1; Exocytosis; Gamma-aminobutyric acid (GABA); Interneuron synapse; Schizophrenia