Gene Dosage in the Dysbindin Schizophrenia Susceptibility Network Differentially Affect Synaptic Function and Plasticity

• Type of Material: Article
• Authors: Ariana P. Mullin, Emory University; Mudhumala K. Sadanandappa, National Centre for Biological Sciences; Wenpei Ma, University of Southern California; Dick K. Dickman, University of Southern California; Krishnaswamy VijayRaghavan, National Centre for Biological Sciences; Mani Ramaswami, Trinity College Dublin; Subhabrata Sanyal, Biogen-Idec; Victor Faundez, Emory University
• Language: English
• Date: 2015-01-07
• Publisher: Society for Neuroscience
• Publication Version: Final Published Version
• Copyright Statement: © 2015 the authors
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1523/JNEUROSCI.3542-14.2015
• Title of Journal or Parent Work: Journal of Neuroscience Nursing
• ISSN: 0270-6474
• Volume: 35
• Issue: 1
• Start Page: 325
• End Page: 338
• Grant/Funding Information: Grants from the National Institutes of Health (GM077569) and in part by the Emory University Integrated Cellular Imaging Microscopy Core and Viral Cores of the Emory Neuroscience National Institute of Neurological Disorders and Stroke Core Facilities Grant (P30NS055077 to V.F.); Grants from Science Foundation Ireland to M.R., Core funds from the NCBS TIFR Centre to K.V.; An INSPIRE fellowship from Department of Science and Technology India and Biocon India Scholarship Programme to M.K.S.
• Keywords: schizophrenia; BLOC-1; olfactory habituation; dysbindin; synaptic vesicle
• Research Categories: Biology, Genetics; Biology, Neuroscience

Abstract

Neurodevelopmental disorders arise from single or multiple gene defects. However, the way multiple loci interact to modify phenotypic outcomes remains poorly understood. Here, we studied phenotypes associated with mutations in the schizophrenia susceptibility gene dysbindin (dysb), in isolation or in combination with null alleles in the dysb network component Blos1. In humans, the Blos1 ortholog Bloc1s1encodesapolypeptide that assembles, with dysbindin, into the octameric BLOC-1 complex.Webiochemically confirmed BLOC-1 presence in Drosophila neurons, and measured synaptic output and complex adaptive behavior in response to BLOC-1 perturbation. Homozygous loss-of-function alleles of dysb, Blos1, or compound heterozygotes of these alleles impaired neurotransmitter release, synapse morphology, and homeostatic plasticity at the larval neuromuscular junction, and impaired olfactory habituation. This mul-tiparameter assessment indicated that phenotypes were differentially sensitive to genetic dosages of loss-of-function BLOC-1 alleles. Our findings suggest that modification of asecond genetic locus in adefined neurodevelopmental regulatory network does not followa strict additive genetic inheritance, but rather, precise stoichiometry within the network determines phenotypic outcomes.