Gene dosage in the dysbindin schizophrenia susceptibility network differentially affect synaptic function and plasticity

• Published in: The Journal of neuroscience Vol. 35; no. 1; pp. 325 - 338
• Main Authors: Mullin, Ariana P, Sadanandappa, Madhumala K, Ma, Wenpei, Dickman, Dion K, VijayRaghavan, Krishnaswamy, Ramaswami, Mani, Sanyal, Subhabrata, Faundez, Victor
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 07-01-2015
• Subjects: Animals; Animals, Genetically Modified; Carrier Proteins - genetics; Drosophila; Drosophila Proteins - genetics; Dysbindin; Dystrophin-Associated Proteins; Female; Gene Dosage - physiology; Nerve Net - physiology; Nerve Net - ultrastructure; Neuronal Plasticity - physiology; Schizophrenia - genetics; Schizophrenia - physiopathology; Synapses - genetics; Synapses - ultrastructure; Synaptic Transmission - physiology; BLOC-1; schizophrenia; dysbindin; olfactory habituation; synaptic vesicle
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.3542-14.2015

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.