PMID- 26386481
OWN - NLM
STAT- MEDLINE
DCOM- 20170830
LR  - 20201021
IS  - 1873-2402 (Electronic)
IS  - 0006-3223 (Linking)
VI  - 80
IP  - 4
DP  - 2016 Aug 15
TI  - Regulation of Brain-Derived Neurotrophic Factor Exocytosis and Gamma-Aminobutyric 
      Acidergic Interneuron Synapse by the Schizophrenia Susceptibility Gene 
      Dysbindin-1.
PG  - 312-322
LID - S0006-3223(15)00684-8 [pii]
LID - 10.1016/j.biopsych.2015.08.019 [doi]
AB  - BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
CI  - Copyright (c) 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All 
      rights reserved.
FAU - Yuan, Qiang
AU  - Yuan Q
AD  - Molecular Neurophysiology Laboratory, Signature Program in Neuroscience and 
      Behavioral Disorders, Duke-National University of Singapore Graduate Medical 
      School, Singapore, Singapore.
FAU - Yang, Feng
AU  - Yang F
AD  - Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, 
      Maryland.
FAU - Xiao, Yixin
AU  - Xiao Y
AD  - Molecular Neurophysiology Laboratory, Signature Program in Neuroscience and 
      Behavioral Disorders, Duke-National University of Singapore Graduate Medical 
      School, Singapore, Singapore.
FAU - Tan, Shawn
AU  - Tan S
AD  - Molecular Neurophysiology Laboratory, Signature Program in Neuroscience and 
      Behavioral Disorders, Duke-National University of Singapore Graduate Medical 
      School, Singapore, Singapore.
FAU - Husain, Nilofer
AU  - Husain N
AD  - Molecular Neurophysiology Laboratory, Signature Program in Neuroscience and 
      Behavioral Disorders, Duke-National University of Singapore Graduate Medical 
      School, Singapore, Singapore.
FAU - Ren, Ming
AU  - Ren M
AD  - Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, 
      Maryland.
FAU - Hu, Zhonghua
AU  - Hu Z
AD  - Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, 
      Maryland.
FAU - Martinowich, Keri
AU  - Martinowich K
AD  - Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, 
      Maryland.
FAU - Ng, Julia S
AU  - Ng JS
AD  - Molecular Neurophysiology Laboratory, Signature Program in Neuroscience and 
      Behavioral Disorders, Duke-National University of Singapore Graduate Medical 
      School, Singapore, Singapore.
FAU - Kim, Paul J
AU  - Kim PJ
AD  - Molecular Neurophysiology Laboratory, Signature Program in Neuroscience and 
      Behavioral Disorders, Duke-National University of Singapore Graduate Medical 
      School, Singapore, Singapore.
FAU - Han, Weiping
AU  - Han W
AD  - Singapore Bioimaging Consortium, Singapore, Singapore.
FAU - Nagata, Koh-Ichi
AU  - Nagata KI
AD  - Institute for Developmental Research, Aichi Human Service Center, Kasugai, Japan.
FAU - Weinberger, Daniel R
AU  - Weinberger DR
AD  - Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, 
      Maryland.
FAU - Je, H Shawn
AU  - Je HS
AD  - 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.
LA  - eng
GR  - R01 MH101102/MH/NIMH NIH HHS/United States
PT  - Journal Article
DEP - 20150828
PL  - United States
TA  - Biol Psychiatry
JT  - Biological psychiatry
JID - 0213264
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (DTNBP1 protein, human)
RN  - 0 (Dysbindin)
RN  - 0 (Dystrophin-Associated Proteins)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Slc32a1 protein, rat)
RN  - 0 (Vesicular Inhibitory Amino Acid Transport Proteins)
RN  - 56-12-2 (gamma-Aminobutyric Acid)
RN  - RWP5GA015D (Potassium)
SB  - IM
MH  - Animals
MH  - Brain-Derived Neurotrophic Factor/*metabolism/pharmacology
MH  - Cell Line, Transformed
MH  - Cells, Cultured
MH  - Cerebral Cortex/cytology
MH  - Dysbindin
MH  - Dystrophin-Associated Proteins/genetics/*metabolism
MH  - Embryo, Mammalian
MH  - Exocytosis/*genetics
MH  - Humans
MH  - Interneurons/drug effects/*metabolism
MH  - Mutation/genetics
MH  - Organ Culture Techniques
MH  - Potassium/pharmacology
MH  - RNA, Small Interfering/genetics/metabolism
MH  - Rats
MH  - Synapses/drug effects/genetics
MH  - Synaptic Potentials/drug effects/genetics
MH  - Vesicular Inhibitory Amino Acid Transport Proteins/metabolism
MH  - gamma-Aminobutyric Acid/metabolism
OTO - NOTNLM
OT  - Brain-derived neurotrophic factor (BDNF)
OT  - DTNBP1
OT  - Dysbindin-1
OT  - Exocytosis
OT  - Gamma-aminobutyric acid (GABA)
OT  - Interneuron synapse
OT  - Schizophrenia
EDAT- 2015/09/21 06:00
MHDA- 2017/08/31 06:00
CRDT- 2015/09/21 06:00
PHST- 2014/10/24 00:00 [received]
PHST- 2015/08/12 00:00 [revised]
PHST- 2015/08/12 00:00 [accepted]
PHST- 2015/09/21 06:00 [entrez]
PHST- 2015/09/21 06:00 [pubmed]
PHST- 2017/08/31 06:00 [medline]
AID - S0006-3223(15)00684-8 [pii]
AID - 10.1016/j.biopsych.2015.08.019 [doi]
PST - ppublish
SO  - Biol Psychiatry. 2016 Aug 15;80(4):312-322. doi: 10.1016/j.biopsych.2015.08.019. 
      Epub 2015 Aug 28.