PT  - JOURNAL ARTICLE
AU  - Avanti Gokhale
AU  - Ariana P. Mullin
AU  - Stephanie A. Zlatic
AU  - Charles A. Easley IV
AU  - Megan E. Merritt
AU  - Nisha Raj
AU  - Jennifer Larimore
AU  - David E. Gordon
AU  - Andrew A. Peden
AU  - Subhabrata Sanyal
AU  - Victor Faundez
TI  - The <em>N</em>-Ethylmaleimide-Sensitive Factor and Dysbindin Interact To Modulate Synaptic Plasticity
AID  - 10.1523/JNEUROSCI.4724-14.2015
DP  - 2015 May 13
TA  - The Journal of Neuroscience
PG  - 7643--7653
VI  - 35
IP  - 19
4099  - http://www.jneurosci.org/content/35/19/7643.short
4100  - http://www.jneurosci.org/content/35/19/7643.full
SO  - J. Neurosci.2015 May 13; 35
AB  - Dysbindin is a schizophrenia susceptibility factor and subunit of the biogenesis of lysosome-related organelles complex 1 (BLOC-1) required for lysosome-related organelle biogenesis, and in neurons, synaptic vesicle assembly, neurotransmission, and plasticity. Protein networks, or interactomes, downstream of dysbindin/BLOC-1 remain partially explored despite their potential to illuminate neurodevelopmental disorder mechanisms. Here, we conducted a proteome-wide search for polypeptides whose cellular content is sensitive to dysbindin/BLOC-1 loss of function. We identified components of the vesicle fusion machinery as factors downregulated in dysbindin/BLOC-1 deficiency in neuroectodermal cells and iPSC-derived human neurons, among them the N-ethylmaleimide-sensitive factor (NSF). Human dysbindin/BLOC-1 coprecipitates with NSF and vice versa, and both proteins colocalized in a Drosophila model synapse. To test the hypothesis that NSF and dysbindin/BLOC-1 participate in a pathway-regulating synaptic function, we examined the role for NSF in dysbindin/BLOC-1-dependent synaptic homeostatic plasticity in Drosophila. As previously described, we found that mutations in dysbindin precluded homeostatic synaptic plasticity elicited by acute blockage of postsynaptic receptors. This dysbindin mutant phenotype is fully rescued by presynaptic expression of either dysbindin or Drosophila NSF. However, neither reduction of NSF alone or in combination with dysbindin haploinsufficiency impaired homeostatic synaptic plasticity. Our results demonstrate that dysbindin/BLOC-1 expression defects result in altered cellular content of proteins of the vesicle fusion apparatus and therefore influence synaptic plasticity.