The schizophrenia susceptibility gene dysbindin controls synaptic homeostasis

Science. 2009 Nov 20;326(5956):1127-30. doi: 10.1126/science.1179685.

Abstract

The molecular mechanisms that achieve homeostatic stabilization of neural function remain largely unknown. To better understand how neural function is stabilized during development and throughout life, we used an electrophysiology-based forward genetic screen and assessed the function of more than 250 neuronally expressed genes for a role in the homeostatic modulation of synaptic transmission in Drosophila. This screen ruled out the involvement of numerous synaptic proteins and identified a critical function for dysbindin, a gene linked to schizophrenia in humans. We found that dysbindin is required presynaptically for the retrograde, homeostatic modulation of neurotransmission, and functions in a dose-dependent manner downstream or independently of calcium influx. Thus, dysbindin is essential for adaptive neural plasticity and may link altered homeostatic signaling with a complex neurological disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Calcium Channels / genetics
  • Calcium Channels / metabolism
  • Carrier Proteins / genetics
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster / genetics*
  • Drosophila melanogaster / physiology*
  • Dysbindin
  • Dystrophin-Associated Proteins
  • Genes, Insect
  • Glutamic Acid / metabolism
  • Homeostasis
  • Humans
  • Mutation
  • Neuromuscular Junction / physiology
  • Neuronal Plasticity
  • Schizophrenia / genetics
  • Synapses / physiology*
  • Synapses / ultrastructure
  • Synaptic Transmission*
  • Synaptic Vesicles / metabolism
  • Transgenes

Substances

  • Calcium Channels
  • Carrier Proteins
  • DTNBP1 protein, human
  • Drosophila Proteins
  • Dysbindin
  • Dystrophin-Associated Proteins
  • cac protein, Drosophila
  • Glutamic Acid
  • Calcium