1. ¹Mental Retardation Research Center, Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA
2. ²Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
3. ³Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
4. ⁴ACCESS Program, University of California, Los Angeles, CA, USA
5. ⁵Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

Correspondence: Dr EC Dell'Angelica, Department of Human Genetics, Gonda Center, Room 6357B, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-7088, USA. E-mail: edellangelica@mednet.ucla.edu; Dr CA Ghiani, Mental Retardation Research Center, Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, 635 Charles E Young Drive South, Los Angeles, CA 90095-7332, USA. E-mail: cghiani@mednet.ucla.edu

⁶These authors contributed equally to this work.

Received 15 December 2008; Revised 8 May 2009; Accepted 26 May 2009; Published online 23 June 2009.

Abstract

Previous studies have implicated DTNBP1 as a schizophrenia susceptibility gene and its encoded protein, dysbindin, as a potential regulator of synaptic vesicle physiology. In this study, we found that endogenous levels of the dysbindin protein in the mouse brain are developmentally regulated, with higher levels observed during embryonic and early postnatal ages than in young adulthood. We obtained biochemical evidence indicating that the bulk of dysbindin from brain exists as a stable component of biogenesis of lysosome-related organelles complex-1 (BLOC-1), a multi-subunit protein complex involved in intracellular membrane trafficking and organelle biogenesis. Selective biochemical interaction between brain BLOC-1 and a few members of the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) superfamily of proteins that control membrane fusion, including SNAP-25 and syntaxin 13, was demonstrated. Furthermore, primary hippocampal neurons deficient in BLOC-1 displayed neurite outgrowth defects. Taken together, these observations suggest a novel role for the dysbindin-containing complex, BLOC-1, in neurodevelopment, and provide a framework for considering potential effects of allelic variants in DTNBP1—or in other genes encoding BLOC-1 subunits—in the context of the developmental model of schizophrenia pathogenesis.