Regulation of Brain-Derived Neurotrophic Factor Exocytosis and Gamma-Aminobutyric Acidergic Interneuron Synapse by the Schizophrenia Susceptibility Gene Dysbindin-1

Qiang Yuan, Feng Yang, Yixin Xiao, Shawn Tan, Nilofer Husain, Ming Ren, Zhonghua Hu, Keri Martinowich, Julia S. Ng, Paul J. Kim, Weiping Han, Koh ichi Nagata, Daniel R. Weinberger, H. Shawn Je

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)312-322
Number of pages11
JournalBiological psychiatry
Volume80
Issue number4
DOIs
StatePublished - Aug 15 2016

Keywords

  • Brain-derived neurotrophic factor (BDNF)
  • DTNBP1
  • Dysbindin-1
  • Exocytosis
  • Gamma-aminobutyric acid (GABA)
  • Interneuron synapse
  • Schizophrenia

ASJC Scopus subject areas

  • Biological Psychiatry

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