title: Gene dosage in the dysbindin schizophrenia susceptibility network differentially affect synaptic function and plasticity.
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 Bloc1s1 encodes a polypeptide that assembles, with dysbindin, into the octameric BLOC-1 complex. We biochemically 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 multiparameter assessment indicated that phenotypes were differentially sensitive to genetic dosages of loss-of-function BLOC-1 alleles. Our findings suggest that modification of a second genetic locus in a defined neurodevelopmental regulatory network does not follow a strict additive genetic inheritance, but rather, precise stoichiometry within the network determines phenotypic outcomes.
authors.affiliation: Department of Cell Biology, Emory University, Atlanta, Georgia 30322.
authors.forename: Ariana P
authors.initials: AP
authors.lastname: Mullin
authors.affiliation: National Centre for Biological Sciences, Bangalore 560065, India.
authors.forename: Madhumala K
authors.initials: MK
authors.lastname: Sadanandappa
authors.affiliation: Department of Biology, Neurobiology Section, University of Southern California, Los Angeles, California 90089.
authors.forename: Wenpei
authors.initials: W
authors.lastname: Ma
authors.affiliation: Department of Biology, Neurobiology Section, University of Southern California, Los Angeles, California 90089.
authors.forename: Dion K
authors.initials: DK
authors.lastname: Dickman
authors.affiliation: National Centre for Biological Sciences, Bangalore 560065, India.
authors.forename: Krishnaswamy
authors.initials: K
authors.lastname: VijayRaghavan
authors.affiliation: School of Genetics and Microbiology, School of Natural Sciences, Smurfit Institute of Genetics and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin-2, Ireland.
authors.forename: Mani
authors.initials: M
authors.lastname: Ramaswami
authors.affiliation: Biogen-Idec, Cambridge, Massachusetts 02142, and.
authors.forename: Subhabrata
authors.initials: S
authors.lastname: Sanyal
authors.affiliation: Department of Cell Biology, Emory University, Atlanta, Georgia 30322, Center for Social Translational Neuroscience, Emory University, Atlanta, Georgia 30322 vfaunde@emory.edu.
authors.forename: Victor
authors.initials: V
authors.lastname: Faundez
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002352:Carrier Proteins / Q000235:genetics*; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics*; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D005260:Female; D018628:Gene Dosage / Q000502:physiology*; D009415:Nerve Net / Q000502:physiology* / Q000648:ultrastructure; D009473:Neuronal Plasticity / Q000502:physiology*; D012559:Schizophrenia / Q000235:genetics* / Q000503:physiopathology; D013569:Synapses / Q000235:genetics* / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000502:physiology
chemical_list: D002352:Carrier Proteins; D029721:Drosophila Proteins; C569104:Dysb protein, Drosophila; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins
keywords: BLOC-1; dysbindin; olfactory habituation; schizophrenia; synaptic vesicle