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.

BLOS2 negatively regulates Notch signaling during neural and hematopoietic stem and progenitor cell development

“…In addition, BLOS2 may have a function in the nucleus (Sun et al, 2008). Second, the residual activity of the destabilized subunit outside of BLOC-1 may function in some way that is different from a null mutation itself, suggesting that phenotypes are differentially sensitive to genetic dosages of loss-of-function BLOC-1 alleles (Mullin et al, 2015). …”

Transmission, Development, and Plasticity of Synapses

“…In mammals and flies, Dysb associates with seven other proteins to form BLOC-1 (biogenesis of lysosome-related organelles), a complex implicated in several aspects of membrane trafficking and fusion (Mullin et al 2011. Genetic interaction experiments support the idea that the BLOC-1 components Snapin and Blos-1 cooperate with Dysb to mediate homeostatic plasticity in Drosophila (Dickman et al 2012;Mullin et al 2015), and like Dysb, Snapin localizes to SVs (Dickman et al 2012). The mechanism of how Dysb and its interactors function in homeostatic compensation is unclear, but might involve regulation of SNARE-mediated fusion events, as BLOC-1 components have been shown to interact with SNAREs and NSF (Ghiani et al 2010;Gokhale et al 2015), and overexpression of NSF rescues the ability to respond to PhTx in dysb mutants (Gokhale et al 2015).…”

Cellular and molecular mechanisms of neurodevelopmental disorders

“…The authors report improvement of cognitive functions and memory by using the sphingolipid Fingolimod in a well‐studied mouse model lacking the dysbindin‐containing complex Biogenesis of lysosome‐organelle complex‐1 (BLOC‐1). Dysbindin was associated with schizophrenia (Straub et al, ) and later found to be part of BLOC‐1 in tissues such as liver (Li et al, ) and brain (Ghiani et al, ), as well as in invertebrates (Mullin et al, ). Even though the genetic association between dysbindin and schizophrenia has not been proven strong (Straub et al, ; Farrell et al, ), several reports have pointed out that this complex may play a role in brain function and, most importantly, including its development (Ryder and Faundez, ; Ghiani and Dell' Angelica ; Mullin et al, ).…”