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Author Notes:

Email Address: Victor Faundez :vfaunde@emory.edu

A.P.M., M.K.S., D.K.D., K.V., M.R., S.S., and V.F. designed research.

A.P.M., M.K.S., M.R., and S.S. performed research.

W.M., D.K.D., K.V., and M.R. contributed unpublished reagents/analytic tools.

A.P.M., M.K.S., K.V., M.R., S.S., and V.F. analyzed data.

A.P.M., M.R., S.S., and V.F. wrote the paper.

We thank Isabell Twick for making the “clean” dysb1 line used here and Raheleh Heidari for valuable preliminary studies of STH in dysb1 mutants.

We are indebted to the Faundez lab members for their comments.

The authors declare no competing financial interests.

Subjects:

Research Funding:

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:

  • BLOC-1
  • dysbindin
  • olfactory habituation
  • schizophrenia
  • synaptic vesicle

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

Tools:

Journal Title:

Journal of Neuroscience Nursing

Volume:

Volume 35, Number 1

Publisher:

, Pages 325-338

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2015 the authors

This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits distribution, public display, and publicly performance, distribution of derivative works, making multiple copies, provided the original work is properly cited. This license requires credit be given to copyright holder and/or author, copyright and license notices be kept intact.

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