InteractiveFly: GeneBrief

dysbindin: Biological Overview | References

Gene name - dysbindin

Synonyms -

Cytological map position - 75E2-75E2

Function - signaling

Keywords - neuromuscular synapse - required presynaptically for the retrograde, homeostatic modulation of neurotransmission, endosome trafficking

Symbol - dysb

FlyBase ID: FBgn0036819

Genetic map position - chr3L:18,860,877-18,862,321

Classification - coiled-coil-containing protein

Cellular location - cytoplasmic

NCBI link: EntrezGene

dysb orthologs: Biolitmine

Recent literature

Gokhale, A., et al. (2015). The N-ethylmaleimide-sensitive factor and dysbindin interact to modulate synaptic plasticity. J Neurosci 35: 7643-7653. PubMed ID: 25972187.
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. This study consisted of a proteome-wide search for polypeptides whose cellular content is sensitive to dysbindin/BLOC-1 loss of function. Components of the vesicle fusion machinery were identified 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, the role for NSF was studied in dysbindin/BLOC-1-dependent synaptic homeostatic plasticity in Drosophila. As previously described, this study 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. These 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.

Furukubo-Tokunaga, K., et al. (2016). DISC1 causes associative memory and neurodevelopmental defects in fruit flies. Mol Psychiatry. PubMed ID: 26976042
Originally found in a Scottish family with diverse mental disorders, the DISC1 protein has been characterized as an intracellular scaffold protein that associates with diverse binding partners in neural development. To explore its functions in a genetically tractable system, the human DISC1 was expressed in fruit flies. Overexpression of DISC1 impairs associative memory. Experiments with deletion/mutation constructs have revealed the importance of amino-terminal domain (46-290) for memory suppression whereas carboxyl domain (598-854) and the amino-terminal residues (1-45) including the nuclear localization signal (NLS1) are dispensable. DISC1 overexpression also causes suppression of axonal and dendritic branching of mushroom body neurons, which mediate a variety of cognitive functions in the fly brain. Analyses with deletion/mutation constructs reveal that protein domains 598-854 and 349-402 are both required for the suppression of axonal branching, while amino-terminal domains including NLS1 are dispensable. In contrast, NLS1 was required for the suppression of dendritic branching, suggesting a mechanism involving gene expression. Moreover, domain 403-596 is also required for the suppression of dendritic branching. Overexpression of DISC1 suppresses glutamatergic synaptogenesis in developing neuromuscular junctions. Deletion/mutation experiments have revealed the importance of protein domains 403-596 and 349-402 for synaptic suppression, while amino-terminal domains including NLS1 are dispensable. Finally, DISC1 functionally interacts with the fly homolog of Dysbindin (DTNBP1) via direct protein-protein interaction in developing synapses.


The molecular mechanisms that achieve homeostatic stabilization of neural function remain largely unknown. To better understand how neural function is stabilized during development and throughout life, an electrophysiology-based forward genetic screen was used, and the function of more than 250 neuronally expressed genes was assessed for a role in the homeostatic modulation of synaptic transmission in Drosophila. This screen ruled out the involvement of numerous synaptic proteins and identified a critical function for dysbindin, a gene linked to schizophrenia in humans. dysbindin was found to be required presynaptically for the retrograde, homeostatic modulation of neurotransmission, and functions in a dose-dependent manner downstream or independently of calcium influx. Thus, dysbindin is essential for adaptive neural plasticity and may link altered homeostatic signaling with a complex neurological disease (Dickman, 2009).

At glutamatergic synapses of species ranging from Drosophila to human, disruption of postsynaptic neurotransmitter receptor function can be precisely offset by an increase in presynaptic neurotransmitter release to homeostatically maintain normal postsynaptic excitation. The Drosophila neuromuscular junction (NMJ) is a glutamatergic synapse that is used as a model for this form of homeostatic signaling in the nervous system. Efficient homeostatic modulation of presynaptic release at the Drosophila NMJ can occur in ten min following bath application of philanthotoxin-433 (PhTx; a polyamine toxin present in the venom sac of the solitary digger wasp Philanthus triangulum), which persistently and specifically inhibits postsynaptic glutamate receptors (Dickman, 2009).

This study has systematically screened for mutations that block the rapid, PhTx-dependent induction of synaptic homeostasis. Mutations in 276 genes were screened electrophysiologically. For each mutant, an average value was calculated for the amplitude of both the spontaneous miniature excitatory junctional potential (mEJP) and evoked excitatory junctional potential (EJP) following treatment of the dissected neuromuscular preparation with PhTx for 10 min. 14 mutants were isolated with average EJP amplitudes more than two standard deviations smaller than the distribution mean. From these candidates, 7 mutants were identified that block synaptic homeostasis without an obvious effect on NMJ morphology or baseline synaptic transmission. It is concluded that the molecular mechanisms of synaptic homeostasis can be genetically separated from the mechanisms responsible for normal neuromuscular development and baseline synaptic transmission (Dickman, 2009).

A fraction of the mutants assayed (19.5%) are previously published genetic lesions. This allows ruling out of the involvement of numerous genes and associated biochemical processes. Mutations that disrupt RNA-interference/micro-RNA processing, retrograde trans-synaptic signaling, synaptic transmission, active zone assembly, synaptic vesicle endocytosis and mitochondria all showed reliable homeostatic compensation. Therefore, synaptic homeostasis is a robust phenomenon, unperturbed by a broad spectrum of synaptic mutations. In addition, significant homeostatic compensation in synaptojanin and endophilin mutants argues against the involvement of synaptic vesicle endocytosis and indicates that the size of the recycling synaptic vesicle pool is not a limiting factor for synaptic homeostasis. These data also emphasize the importance and specificity of those identified mutations that do block synaptic homeostasis. These include four ion channels, two of which are of unknown function, and two calcium-binding proteins of unknown function. Thus, homeostatic signaling at the NMJ may include previously unexplored mechanisms of synaptic modulation (Dickman, 2009).

One mutation that was identified with a specific defect in homeostatic compensation is a transposon insertion that resides in the Drosophila homologue of dysbindin (CG6856). The DTNBP1 (dysbindin) locus is linked with schizophrenia in humans (Ross, 2006). A transposon insertion was identified within the dysbindin locus (pBace01028, referred to as dysb1, that showed a complete absence of homeostatic compensation following application of PhTx. A similar effect was observed when dysb1 was placed in trans to a deficiency that uncovers the dysb locus, indicating that the dysb1 mutant was a strong loss of function or null mutation. No significant change in baseline synaptic transmission was observed in dysb1 mutant animals (0.5 mM extracellular calcium). Thus, under these recording conditions, this mutation disrupted synaptic homeostasis without altering baseline neurotransmission. As a control, synaptic homeostasis was normal in animals in which the pBace01028 transposon was precisely excised (Dickman, 2009).

The dysb gene is ubiquitously expressed in Drosophila embryos. Therefore, a dysbindin transgene was generated and expressed in the dysb1 mutant. Presynaptic expression of dysb fully restored homeostatic compensation in the dysb1 mutant background, whereas muscle-specific expression of dysb did not. Thus, Dysbindin is necessary presynaptically for the rapid induction of synaptic homeostasis (Dickman, 2009).

It was next asked whether Dysbindin is also required for the sustained expression of synaptic homeostasis. Double mutant animals were generated harboring both the dysb1 mutation and a mutation in a gene encoding a postsynaptic glutamate receptor (GluRIIA). GluRIIA mutant animals normally show robust homeostatic compensation. However, homeostatic compensation was blocked in GluRIIA; dysb1 double mutant animals. Thus, dysbindin was also necessary for the sustained expression of synaptic homeostasis over several days of larval development (Dickman, 2009).

Synapse morphology was qualitatively normal in dysb mutants including both the shape of the presynaptic nerve terminal and the levels, localization and organization of synaptic markers including futsch-positive microtubules, synapsin and synaptotagmin. Bouton number and active zone density are also normal in dysb mutants. Thus, the disruption of synaptic homeostasis in dysb1 mutants is not a secondary consequence of altered or impaired NMJ development (Dickman, 2009).

In the vertebrate nervous system, Dysbindin is associated with synaptic vesicles (Talbot, 2006). The localization was examined of a Venus-tagged dysb transgene (ven-dysb) that rescues the dysb1 mutant. Ven-Dysb showed extensive overlap with synaptic vesicle associated proteins when expressed in neurons. Thus, Dysbindin functions presynaptically, potentially at or near the synaptic vesicle pool (Dickman, 2009).

To further define the function of Dysbindin, baseline synaptic transmission in the dysb mutant was investigated in greater detail. At 0.5 mM extracellular calcium, synaptic transmission in dysb1 mutant animals was indistinguishable from wild type. However, when extracellular calcium was reduced, baseline synaptic transmission was significantly impaired in dysb compared to wild type and this defect was rescued by presynaptic expression of dysb. Thus, there is an alteration of the calcium dependence of synaptic transmission in the dysb mutant. Indeed, at reduced extracellular calcium, both paired-pulse facilitation and facilitation that occurs during a prolonged stimulus train were increased in dysb mutants (Dickman, 2009).

In vertebrates, the levels of dysb expression correlate with parallel changes in extracellular glutamate concentration (Numakawa, 2004). Therefore, whether dysb overexpression might increase presynaptic release was tested. In wild-type animals overexpressing dysb in neurons, synaptic transmission is normal at low extracellular calcium (0.2 and 0.3 mM Ca2+) but was enhanced at relatively higher extracellular calcium (0.5 mM Ca2+). The complementary effects of dysb loss-of-function and overexpression confirm that Dysbindin has an important influence on calcium-dependent vesicle release (Dickman, 2009).

The presynaptic CaV2.1 calcium channel, encoded by cacophony (cac), is required for synaptic vesicle release at the Drosophila NMJ. cac mutations decrease presynaptic calcium influx and also block synaptic homeostasis. Genetic interaction between dysb and cac was tested during synaptic homeostasis. Because homozygous cac and dysb mutations individually block synaptic homeostasis, analysis of double mutant combinations would not be informative. An analysis of heterozygous mutant combinations and gene overexpression were examined. Synaptic homeostasis was suppressed by a heterozygous mutation in cac. However, this suppression was not enhanced by the presence of a heterozygous mutation in dysb. In addition, neuronal overexpression of cac did not restore homeostatic compensation in dysb mutant animals and the enhancement of presynaptic release caused by neuronal dysb overexpression still occurs in a heterozygous cac mutant background. Thus, Dysbindin may function downstream or independently of Cac during synaptic homeostasis (Dickman, 2009).

To further explore the relationship between Dysbindin and Cac, it was asked whether dysb mutations might directly influence presynaptic calcium influx. The spatially averaged calcium signal in dysb1 was indistinguishable from wild type, indicating no difference in presynaptic calcium influx. Thus, Dysbindin appears to function downstream or independently of calcium influx to control synaptic homeostasis (Dickman, 2009).

Through a systematic electrophysiological analysis of more than 250 mutants this study could rule out the involvement of numerous synaptic proteins and biochemical processes in the mechanisms of synaptic homeostasis and demonstrate that this phenomenon is separable from the molecular mechanisms that specify structural and functional synapse development. Dysbindin is therefore identified as an essential presynaptic component within a homeostatic signaling system that regulates and stabilizes synaptic efficacy. Dysbindin functions downstream or independently of the presynaptic CaV2.1 calcium channel in the mechanisms of synaptic homeostasis (Dickman, 2009).

Emerging lines of evidence suggest that glutamate hypofunction could be related to the etiology of schizophrenia. Likewise, reduced levels of dysbindin expression were associated with schizophrenia (Weickert, 3008; Talbot, 2004). The sandy mouse, which lacks Dysbindin, has a decreased rate of vesicle release (~30% decrease), a correlated decrease in vesicle pool size and an increased thickness of the postsynaptic density (Chen, 2008). This study confirms a modest, facilitatory function for Dysbindin during baseline transmission. However, numerous mutations with similar or more severe defects in baseline transmission show normal synaptic homeostasis. By contrast, loss of Dysbindin completely blocks the adaptive, homeostatic modulation of vesicle release, suggesting that the potential contribution of dysbindin mutations to schizophrenia may be derived from altered homeostatic plasticity as opposed to decreased baseline glutamatergic transmission (Dickman, 2009).

The schizophrenia susceptibility factor Dysbindin and its associated complex sort cargoes from cell bodies to the synapse

Dysbindin assembles into the biogenesis of lysosome related organelles complex 1 (BLOC-1), which interacts with the adaptor protein complex 3 (AP-3) mediating a common endosome trafficking route. Deficiencies in AP-3 and BLOC-1 affect synaptic vesicle composition. However, whether AP-3-BLOC-1-dependent sorting events that control synapse membrane protein content take place in cell bodies, upstream nerve terminals, remains unknown. This study tested this hypothesis analyzing the targeting of phosphatidylinositol-4-kinase type II α (PI4KIIα), a membrane protein present in pre and postsynaptic compartments. PI4KIIα co-purified with BLOC-1 and AP-3 in neuronal cells. These interactions translated into a decreased PI4KIIα content in the dentate gyrus of dysbindin-null BLOC-1 deficiency, and AP-3-null mice. Reduction of PI4KIIα in the dentate reflects a failure to traffic from the cell body. PI4KIIα was targeted to processes in wild type primary cultured cortical neurons and PC12 cells, but failed to reach neurites in cells lacking either AP-3 or BLOC-1. Similarly, disruption of an AP-3 sorting motif in PI4KIIα impaired its sorting into processes of PC12 and primary cultured cortical neuronal cells. These findings indicate a novel vesicle transport mechanism requiring BLOC-1 and AP-3 complexes for cargo sorting from neuronal cell bodies to neurites and nerve terminals (Larimore, 2011).

Nucleocytoplasmic shuttling of dysbindin-1, a schizophrenia-related protein, regulates synapsin I expression

Dysbindin-1 is a 50-kDa coiled-coil-containing protein encoded by the gene DTNBP1 (dystrobrevin-binding protein 1), a candidate genetic factor for schizophrenia. Genetic variations in this gene confer a susceptibility to schizophrenia through a decreased expression of dysbindin-1. It was reported that dysbindin-1 regulates the expression of presynaptic proteins and the release of neurotransmitters. However, the precise functions of dysbindin-1 are largely unknown. This study shows that dysbindin-1 is a novel nucleocytoplasmic shuttling protein and translocated to the nucleus upon treatment with leptomycin B, an inhibitor of exportin-1/CRM1-mediated nuclear export. Dysbindin-1 harbors a functional nuclear export signal necessary for its nuclear export, and the nucleocytoplasmic shuttling of dysbindin-1 affects its regulation of synapsin I expression. In brains of sandy mice, a dysbindin-1-null strain that displays abnormal behaviors related to schizophrenia, the protein and mRNA levels of synapsin I are decreased. These findings demonstrate that the nucleocytoplasmic shuttling of dysbindin-1 regulates synapsin I expression and thus may be involved in the pathogenesis of schizophrenia (Fei, 2010).

Schizophrenia susceptibility gene dysbindin regulates glutamatergic and dopaminergic functions via distinctive mechanisms in Drosophila

The dysfunction of multiple neurotransmitter systems is a striking pathophysiological feature of many mental disorders, schizophrenia in particular, but delineating the underlying mechanisms has been challenging. This study shows that manipulation of a single schizophrenia susceptibility gene, dysbindin, is capable of regulating both glutamatergic and dopaminergic functions through two independent mechanisms, consequently leading to two categories of clinically relevant behavioral phenotypes. Dysbindin has been reported to affect glutamatergic and dopaminergic functions as well as a range of clinically relevant behaviors in vertebrates and invertebrates but has been thought to have a mainly neuronal origin. This study found that reduced expression of Drosophila dysbindin (dysb) in presynaptic neurons significantly suppresses glutamatergic synaptic transmission and that this glutamatergic defect is responsible for impaired memory. However, only the reduced expression of Dysb in glial cells is the cause of hyperdopaminergic activities that lead to abnormal locomotion and altered mating orientation. This effect is attributable to the altered expression of a dopamine metabolic enzyme, Ebony, in glial cells. Thus, Dysb regulates glutamatergic transmission through its neuronal function and regulates dopamine metabolism by regulating Ebony expression in glial cells (Shao, 2011).

The current study investigated functions of Ddysb to explore how the altered expression of a single schizophrenia susceptibility gene relates to the pathophysiology and clinically relevant phenotypes. The function of this gene is highly conserved from Drosophila to vertebrates and even to humans. The observed pattern of dysb expression in the Drosophila brain is very similar to that reported in the vertebrate brain: widespread and enriched in neurons. Loss-of-function mutations and RNAi knockdown of dysb in Drosophila produced phenotypes similar to those observed in the sandy mouse, including attenuated glutamatergic transmission, hyperdopaminergic activity, memory defects, and locomotor hyperactivity. Moreover, the human DTNBP1 gene was capable of rescuing dysb1 mutant phenotypes in Drosophila. With the help of genetic tools exclusively available in Drosophila, however, surprising insights were gained (Shao, 2011).

First, although Dysb is widely expressed in the brain, restoring Dysb in glutamatergic neurons alone was sufficient to rescue hypoglutamatergic transmission and memory defects. Second, Dysb's functions in glial cells are essential for normal dopaminergic activity and associated behaviors, including locomotion and mating orientation. Third, all observed pathophysiological and behavioral phenotypes were rescued with acute genetic or pharmacological treatments in adults (Shao, 2011).

Special attention was devoted to validating the phenotypes observed, including maintaining an isogenic background for all genotypes, balancing the behavioral assays, and confirming the manifested phenotypes by different genetic manipulations (mutations, genetic rescuing, and RNAi knockdown). (Shao, 2011).

An increasing number of studies suggest that genetic variation in DTNBP1 in normal human populations affects verbal and visual memories as well as working memory. This association is supported by studies on the sandy mouse, which is defective in a range of memory tasks, including spatial memory, novel object recognition, and contextual fear conditioning . However, the physiological causes of such memory defects are not clearly defined (Shao, 2011).

This study showed that altered dysb function in glutamatergic neurons alone is responsible for attenuated glutamatergic transmission and for the memory defect. It is interesting that this memory defect is not a developmental phenotype and could be rescued acutely both by feeding flies with the NMDA receptor agonist glycine and by expressing dysb only in glutamatergic neurons. Such a result is consistent with reports showing that NMDA receptors in the Drosophila brain are involved in memory formation (Shao, 2011).

Before the current study, the expression and function of dysbindin were considered to occur primarily, if not exclusively, in neurons. However, recent reports have demonstrated that in mouse and rat brains the expression level of dysbindin in glia is comparable with, if not higher than, its expression in neurons, although its glial functions remained to be determined. Genetic tools available for Drosophila allowed definition of the function of dysbindin in glia but also gaining of insight into the underlying mechanisms (Shao, 2011).

Anatomically, it was shown that immunohistochemical signals of Dysb were detected in glial cells labeled by GFP-tagged membrane proteins, with sparse Dysb distribution in cell bodies and the majority of glial Dysb signals in glial processes or in thin layers surrounding individual neuronal cell bodies. This observation was supported by the distribution pattern of VFP-tagged Dysb in GFP-labeled glial cells (Shao, 2011).

Evidence supporting a functional role of Dysb in glia is very strong. The escalated dopamine level in the dysb1 mutant could be rescued by targeted expression of the dysb or human DTNBP1 transgene only in glial cells but not in neurons. In addition, the hyperdopaminergia-elicited behaviors, including locomotor hyperactivity and mating disorientation, were rescued only through targeted glial expression of dysb or human DTNBP1 transgenes. More convincingly, knocking down dysb universally or in glia but not in neurons resulted in embryonic or pupal lethality, respectively (Shao, 2011).

Further investigation suggests that mutations of dysb cause hyperdopaminergic activity by down-regulating the expression of Ebony. The biochemical data profiling mRNA and protein expression corroborated well with genetic observations, supporting the idea that Ebony plays critical role in mediating the effects of Dysb in glial cells. It is likely that this Dysb/Ebony-produced hyperdopaminergic activity somehow leads to reduced TH and Tan expression in neurons through a negative feedback mechanism for maintaining the homeostasis of dopaminergic activity (Shao, 2011).

How Dysb regulates expression of Ebony remains to be determined. One possibility comes from reports that human dysbindin can function as a nucleocytoplasmic shuttling protein that regulates the transcription of several genes either directly or by binding with other transcription-related factors. This study analyzed the Dysb protein sequence with the PSORT II Prediction WWW Server and found that the probability that Dysb localizes to the nucleus is 94.1%. Thus, it is plausible that Dysb in glia plays a role in regulating gene transcription (Shao, 2011).

Alternatively, Dysb might regulate the dopamine level in glial cells by affecting the stability of the Ebony protein. The dysbindin-containing BLOC-1 complex is a component of the endosomal protein sorting and compartmental machinery. Abnormalities in Ebony protein sorting may lead to abnormalities in ubiquitylation, protein instability, or malfunction of the enzyme (Shao, 2011).

Although the possibility of generating fly models of schizophrenia has been raised recently, the intent of this study is not to model schizophrenia in Drosophila. Instead, it was of interest to discover whether and how a single mild genetic alteration, similar to those observed in cases of schizophrenia, gives rise to complex phenotypes at the neurotransmitter regulation and behavioral levels. This study led to two interesting observations (Shao, 2011).

First, it was surprising to see that a rather mild 30%-40% reduction in dysb expression led to significant alterations in both glutamatergic transmission and dopaminergic activity. Most schizophrenia susceptibility genes reported to date are identified not from mutations but from single-nucleotide polymorphisms or haplotypes, which are believed to produce only mild alterations at the gene expression level. It therefore is debatable how strong the contribution of an individual genetic variant is and whether multiple genetic components acting in concert are needed for the effects. This study shows that a mild reduction of at least one of the susceptibility genes is sufficient to cause complex changes in multiple neurotransmitter systems through very different mechanisms. These findings suggest that these susceptibility genes might play such critical roles in neurotransmitter regulation that a mild change in expression is sufficient to cause detectable behavioral phenotypes (Shao, 2011).

Second, although a developmental role of dysbindin has been reported earlier and is supported, as mentioned above, both neurotransmitter and behavioral phenotypes examined in this study could be rescued through acute treatments. Schizophrenia is considered a neurodevelopmental disorder, a notion that is supported by animal model studies of development and by genetic mouse models of neurodevelopmental candidate genes and susceptibility genes. However, this study suggests that, to some extent, some of the genetically relevant phenotypes are reversible or could be treated in adults (Shao, 2011).

Snapin is critical for presynaptic homeostatic plasticity

The molecular mechanisms underlying the homeostatic modulation of presynaptic neurotransmitter release are largely unknown. An electrophysiology-based forward genetic screen has been sued to assess the function of >400 neuronally expressed genes for a role in the homeostatic control of synaptic transmission at the neuromuscular junction of Drosophila melanogaster. This screen identified a critical function for dysbindin, a gene linked to schizophrenia in humans. Biochemical studies in other systems have shown that Snapin interacts with Dysbindin, prompting a test of whether Drosophila Snapin might be involved in the mechanisms of synaptic homeostasis. This study demonstrates that loss of snapin blocks the homeostatic modulation of presynaptic vesicle release following inhibition of postsynaptic glutamate receptors. This is true for both the rapid induction of synaptic homeostasis induced by pharmacological inhibition of postsynaptic glutamate receptors, and the long-term expression of synaptic homeostasis induced by the genetic deletion of the muscle-specific GluRIIA glutamate receptor subunit. Loss of snapin does not alter baseline synaptic transmission, synapse morphology, synapse growth, or the number or density of active zones, indicating that the block of synaptic homeostasis is not a secondary consequence of impaired synapse development. Additional genetic evidence suggests that snapin functions in concert with dysbindin to modulate vesicle release and possibly homeostatic plasticity. Finally, genetic evidence is provided that the interaction of Snapin with SNAP25, a component of the SNARE complex, is also involved in synaptic homeostasis (Dickman, 2012).

This study provides evidence that Snapin promotes the homeostatic modulation of presynaptic neurotransmitter release, functioning presynaptically in concert with Dysbindin and SNAP25. It is important to emphasize that snapin-null mutations have not been examined and, therefore, direct comparisons cannot be made to the synaptic transmission phenotypes observed in snapin mutant mice. However, despite the limitation of assaying only the loss of snapin, it was possible to conclude that reduced levels of snapin expression lead to the block in homeostatic plasticity without dramatically altering baseline transmission. It is concluded that Snapin could impose homeostatic regulation on SNARE-mediated fusion events via an interaction with S Snapin may have in evoked synaptic vesicle fusion (Dickman, 2012).

Several lines of evidence are provided that snapin functions with the schizophrenia susceptibility gene dysbindin, most likely within motoneurons, where both Snapin and Dysbindin have been demonstrated to be required for homeostatic plasticity. In particular, it was demonstrated that the ability of Dysbindin to potentiate synaptic transmission requires normal snapin expression. An interesting possibility, based purely on genetic data, is that Snapin promotes signaling between cytosolic Dysbindin and SNAP25, influencing vesicle release either directly or indirectly. This raises the intriguing possibility that this could be an important site of molecular regulation underlying the homeostatic modulation of presynaptic vesicle release. Indeed, separate studies have reported that changes in both dysbindin and snapin expression alter SNAP25 levels in the nervous system. Future in vivo imaging experiments will be required to directly test this possibility. These are important but challenging experiments and beyond the scope of the present study (Dickman, 2012).

The molecular function of Snapin remains poorly understood in the nervous system and in other tissues. snapin is highly conserved throughout evolution from invertebrates to rodents and human. snapin is ubiquitously expressed in these organisms and does not seem to be enriched within the nervous system. In addition, Snapin protein is present at low levels within neurons compared with other SNARE complex proteins including SNAP25. These observations have led some groups to question whether Snapin has a specific or primary function during SNARE-mediated synaptic vesicle fusion. Ultimately, genetic studies may be required to highlight the primary functions of this molecule. The recent generation of snapin mutant mice has demonstrated a dramatic effect on synchronized vesicle release (Tian, 2005; Pan, 2009) and endosomal transport (Cai, 2010). Neurodegeneration is also reported in these mutants (Dickman, 2012).

In snapin mutant mice, evoked synaptic transmission at physiological calcium is decreased by ~75%, the synchrony of vesicle fusion is impaired, and there is a dramatic reduction in the rate of spontaneous vesicle fusion (Pan, 2009). These data clearly demonstrate that Snapin has a critical role in baseline neurotransmission. This function appears to be mediated through molecular interactions with both SNAP25 and Synaptotagmin1. However, because baseline transmission is so severely perturbed in the mouse mutant, it is difficult to assess whether Snapin might also participate in various forms of neural plasticity beyond the short-term modulation of vesicle release during short trains of stimuli (Dickman, 2012).

This loss-of-function analysis of snapin in Drosophila highlights a unique function during the homeostatic modulation of neurotransmission. This function of Snapin may also be mediated through its interaction with SNAP25, based on the observation that animals that are doubly heterozygous for mutations in snapin and snap25 lack the expression of homeostatic plasticity without a major defect in baseline neurotransmission. An interesting possibility is that Snapin could impose homeostatic regulation on SNARE-mediated fusion events via an interaction with SNAP25. This may, in fact, represent a common function of Snapin in other systems that are also under homeostatic control, including the regulation of calcium stores in nonneural cells. However, based on genetic interaction data, the possibility cannot be ruled out that SNAP25 functions in parallel to Snapin during homeostatic plasticity (Dickman, 2012).

Recently, genetic studies have begun to identify genes that are necessary for the homeostatic control presynaptic neurotransmitter release at the Drosophila NMJ. In each example, a gene mutation prevents the homeostatic modulation of presynaptic release following perturbation of postsynaptic glutamate receptor function. Several mutations have been identified that disrupt baseline neurotransmission without altering the capacity to express synaptic homeostasis, including cystein string protein, methuselah, and Hsc70. Thus, mutations that disrupt basal neurotransmission can be distinguished from those specifically involved in synaptic homeostasis by examining the effects of a mutation before and after disruption of glutamate receptor function. A growing list of genes fit these criteria for being involved in homeostatic plasticity within the presynaptic nerve terminal, including the cacophony (CaV2.1) calcium channel, EphR-ephexin-cdc42 signaling, dysbindin, Rab3-GAP, gooseberry, the miR-310 group, and Khc-73. This study has implicated snapin and possibly snap25 (Dickman, 2012).

A challenge for future studies will be to determine how the functions of these molecules are coordinated within a robust homeostatic signaling system capable of precisely tuning neurotransmission over a broad physiological range. It seems likely that the presynaptic calcium channel will be a focal point of this signaling system. However, some of these molecules may identify additional layers of modulation including dysbindin, snapin, and snap25. Furthermore, miR-310 and Khc-73 have been proposed to regulate active zone structure, which could have a direct effect on calcium channels or other parameters that modulate vesicle release. A further challenge will be to determine not only whether or not these molecules are necessary, but how they normally participate in the induction and expression of a homeostatic change in presynaptic release. Ultimately, these molecular studies will need to be combined with physiological understanding of this process and with new imaging approaches to visualize the dynamic molecular interactions in vivo that drive homeostatic plasticity (Dickman, 2012).

The N-ethylmaleimide-sensitive factor and dysbindin interact to modulate synaptic plasticity

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. This study consisted of a proteome-wide search for polypeptides whose cellular content is sensitive to dysbindin/BLOC-1 loss of function. Components of the vesicle fusion machinery were identified 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, the role for NSF was studied in dysbindin/BLOC-1-dependent synaptic homeostatic plasticity in Drosophila. As previously described, this study 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. These 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 (Gokhale, 2015).

Dysbindin associates with seven other polypeptides to form the biogenesis of lysosome-related organelles complex 1. Null mutations in mouse dysbindin reduce the expression of other BLOC-1 subunit mRNAs and polypeptides. This suggests that dysbindin genetic downregulation could elicit multiple alterations of protein content in cells. This study identified 224 proteins whose content was modified by dysbindin/BLOC-1 partial loss of function using unbiased quantitative mass spectrometry. The screen prominently identified components of the N-ethylmaleimide-sensitive factor (NSF)-dependent vesicle fusion machinery. Focus was placed on NSF, a catalytic component of the fusion machinery, and it was asked whether NSF participates in dysbindin/BLOC-1-dependent synaptic mechanisms. Drosophila presynaptic plasticity produced by the inhibition of postsynaptic receptors was used as an assay. As previously, it was observed that mutations in fly dysbindin precluded the establishment of homeostatic synaptic plasticity, a phenotype that is rescued by presynaptic expression of dysbindin. Neuron-specific expression of dNSF1, the gene encoding Drosophila NSF, by itself does not modulate this form of plasticity, yet NSF1 expression at the synapse of dysbindin mutants rescued homeostatic synaptic plasticity defects to the same extent as dysbindin re-expression in the presynaptic compartment. These results demonstrate that partial dysbindin/BLOC-1 loss of function alters the cellular content of proteins that specifically have roles in synaptic mechanisms (Gokhale, 2015).

Genetic polymorphisms associated with schizophrenia mostly reside in noncoding regions modifying gene and/or protein levels rather protein sequence. The question of how widespread the effects are of a single mutation or polymorphism across the proteome has been poorly explored. This study addressed this question by modeling a partial reduction in the cellular content of dysbindin/BLOC-1 using shRNAs against BLOC-1 complex subunits. 224 proteins were whose content is affected by a partial loss of function of dysbindin/BLOC-1 and focused on an interactome centered around a schizophrenia susceptibility gene, dysbindin, and NSF, a component of the membrane fusion machinery that localizes to the synapse and was previously implicated in schizophrenia mechanisms. Functional outcomes of the dysbindin/BLOC-1 and NSF association were confirmed using a Drosophila synaptic adaptive response. The results demonstrate that dysbindin/BLOC-1 expression defects induce multiple downstream quantitative protein expression traits associated with the vesicle fusion apparatus, which influence synaptic plasticity in an invertebrate model synapse (Gokhale, 2015).

A proteomic search prominently highlights the following components of the vesicle fusion apparatus: munc18, tomosyn, NSF; and the SNAREs syntaxin 7, syntaxin 17, SNAP23, SNAP25, SNAP 29, and VAMP7. Importantly, most of the aforementioned vesicle fusion machinery components have been implicated by genomic and postmortem studies in several neurodevelopmental disorders, including schizophrenia, intellectual disability, and autism spectrum disorder. The current strategy is validated by the identification of proteins previously known to be downregulated in null alleles of BLOC-1 subunits and/or known to interact with BLOC-1. These proteins include subunits of the BLOC-1 complex and the SNARE VAMP7. This study further authenticated these fusion machinery components as part of a dysbindin/BLOC-1 network by (1) coimmunoprecipitation of a fusion machinery component with dysbindin/BLOC-1 subunits and/or (2) downregulation of a fusion machinery component after genetic or shRNA-mediated reduction of dysbindin/BLOC-1 subunits. NSF was studied since it is a hub of protein-protein interactions with components of the fusion machinery, and is a catalytic activity that is required for the resolution of fusion reaction products and other protein-protein complexes. NSF was found to associate with dysbindin and BLOC-1 subunits in neuroblastoma cells in culture. However, efforts to document the association of NSF and dysbindin-BLOC-1 by immunoprecipitation with NSF antibodies were unsuccessful in brain. This outcome occurred regardless of whether NSF was immunoprecipitated from brain homogenates or cross-linked synaptosomal lysates from adult mouse brain. This negative result is attributed to the high abundance of NSF in brain compared with dysbindin/BLOC-1. Reverse immunoprecipitations with dysbindin/BLOC-1 antibodies were not possible, as none of the available antibodies were suitable for immunoprecipitation. Since most of the associations between NSF and dysbindin/BLOC-1 are detected in the presence of the cross-linker DSP in cell lines, it is likely that the biochemical interactions between NSF and dysbindin/BLOC-1 are indirect. However, NSF cellular levels are decreased following shRNA-mediated or genomic reduction of BLOC-1 complex members, arguing in favor of a functional outcome of this association. No NSF downregulation phenotype was detected in hippocampal extracts of Bloc1s8sdy/sdy mice at days 7 or 50 of postnatal development. This suggests that NSF phenotypes may be anatomically restricted either to a region of the hippocampus or to an earlier and transient developmental stage. However, this reduced NSF trait is robustly and reversibly induced by genetic disruption of the dysbindin/BLOC-1 complex or by downregulation of dysbindin/BLOC-1 subunits in neuroblastoma and human embryonic kidney cells, neuroectodermal cells, and iPSC-derived human neurons (Gokhale, 2015).

These studies indicate that the functional outcome of NSF reduction in BLOC-1 loss of function become evident only when the synapse is challenged. Constitutive secretion in Drosophila or mammalian non-neuronal cells is unaffected, as are spontaneous and evoked neurotransmission at the Drosophila neuromuscular junction. However, a requirement for NSF in BLOC-1 loss-of-function phenotypes can be localized to a presynaptic homeostatic mechanism, which is engaged when postsynaptic receptors are blocked with philanthotoxin. After a brief incubation with philanthotoxin, the resultant reduction in postsynaptic signal transduction rapidly induces a compensatory increase in quantal content, a response known as homeostatic synaptic plasticity. This adaptive compensatory mechanism is precluded by dysbindin mutations, and can be rescued by presynaptic expression of dysbindin. However, it was possible to rescue this phenotype in the dysbindin mutants to the exact same extent through presynaptic expression NSF. The observation that RNAi downregulation or overexpression of NSF in the neuromuscular junction does not interfere with homeostatic synaptic plasticity argues that the NSF is not an obligate component downstream of dysbindin/BLOC-1 in a linear pathway, but rather is an adaptive response to network perturbation induced by a dysbindin mutant allele. This hypothesis predicts that transheterozygotic reduction of NSF and Dysbindin should impair plasticity, a result that is at odds with the finding that plasticity is normal in dysb1-/+;UAS-NSF RNAi. It is believe that this may be a consequence of a modest reduction of dysbindin polypeptide in dysb1-/+ animals, which was predicted to be ~25% (Gokhale, 2015).

How does the BLOC-1-NSF interaction affect synaptic mechanisms? A model integrating these findings has to consider three key elements. First, BLOC-1 subunits reside at endosomes as well as on synaptic vesicles in presynaptic terminals in neurons. Second, BLOC-1 binds monomeric SNAREs rather than tetrahelical SNARE bundles in vitro. Finally, NSF and SNAREs bind to dysbindin/BLOC-1, yet they do not seem to form a ternary complex. Thus, it is proposed that BLOC-1 bound to a single SNARE (perhaps for SNARE sorting into vesicles) is resolved by NSF, making SNAREs permissive for vesicle fusion. Therefore, when dysbindin and NSF levels are reduced by hypomorphic mutations in the fly or as a quantitative expression trait in humans, SNARE-dependent mechanisms might be impaired due to defective SNARE sorting, a consequence of the reduced levels of BLOC-1 complex and, additionally, by decreased NSF content that would impair the resolution of remaining SNARE-BLOC-1 complexes. Thus, noncoding polymorphisms in several genes and their quantitative expression traits may converge to impair synaptic mechanisms. It is proposed that unbiased identification of quantitative traits across the proteome of neurodevelopmental deficiency models is a simple approach to unravel mechanisms of complex neurodevelopmental disorders (Gokhale, 2015).

Dysbindin links presynaptic proteasome function to homeostatic recruitment of low release probability vesicles

This study explores the relationship between presynaptic homeostatic plasticity and proteasome function at the Drosophila neuromuscular junction. First, it was demonstrated that the induction of homeostatic plasticity is blocked after presynaptic proteasome perturbation. Proteasome inhibition potentiates release under baseline conditions but not during homeostatic plasticity, suggesting that proteasomal degradation and homeostatic plasticity modulate a common pool of vesicles. The vesicles that are regulated by proteasome function and recruited during homeostatic plasticity are highly EGTA sensitive, implying looser Ca2+ influx-release coupling. Similar to homeostatic plasticity, proteasome perturbation enhances presynaptic Ca2+ influx, readily-releasable vesicle pool size, and does not potentiate release after loss of specific homeostatic plasticity genes, including the schizophrenia-susceptibility gene dysbindin. Finally, genetic evidence is provided that Dysbindin levels regulate the access to EGTA-sensitive vesicles. Together, these data suggest that presynaptic protein degradation opposes the release of low-release probability vesicles that are potentiated during homeostatic plasticity and whose access is controlled by dysbindin (Wentzel, 2018).

At the Drosophila NMJ, PHP can be rapidly induced within minutes in the presence of the protein synthesis inhibitor cyclohexamide, suggesting that the acute induction of PHP does not require synthesis of new proteins. In contrast, protein degradation has not been studied in the context of PHP at this synapse. The ubiquitin-proteasome system (UPS) is a major protein degradation pathway. At the Drosophila NMJ it has been shown that all components of the UPS are present at presynaptic terminals and that acute proteasome inhibition causes a rapid strengthening of neurotransmission There is accumulating evidence for links between neural activity and UPS-mediated degradation of presynaptic proteins in mice and rats. However, only two presynaptic proteins -- Rab3-interacting molecule (RIM: Jiang, 2010; Lazarevic, 2011; Yao, 2007) and Dunc-13/munc-13 (Speese, 2003) -- as well as one E3-ligase (SCRAPPER Yao, 2007) have so far been implicated in UPS-dependent control of presynaptic protein turnover and release. Thus, the molecular pathways underlying the regulation of presynaptic release through protein degradation remain enigmatic (Wentzel, 2018).

PHP at the Drosophila NMJ requires high-release probability (pr) vesicles that are 'tightly coupled' to Ca2+ channels through rim-binding protein. The distance between Ca2+ channels and Ca2+ sensors of exocytosis, typically referred to as 'coupling distance', is a major factor determining the pr of synaptic vesicles. However, despite their implication in short-term plasticity, little is known about how vesicles that are differentially coupled to Ca2+ influx are modulated during synaptic plasticity (Wentzel, 2018).

This study explored the relationship between PHP and presynaptic proteasome function at the Drosophila NMJ and provides evidence for links between presynaptic protein degradation and homeostatic potentiation of loosely-coupled synaptic vesicles (Wentzel, 2018).

Rapid effects of proteasome perturbation were observed on neurotransmitter release and the abundance of ubiquitinated proteins on the minute time scale. These data suggest that the proteasomal degradation rate is relatively high under baseline conditions, consistent with previous work on local protein degradation in the presynaptic or postsynaptic compartment, and considerably faster than the average neuron-wide turnover rates of synaptic proteins (2-5 days). Such rapid degradation rates could in turn allow for potent modulation of protein abundance and/or ubiquitination through regulation of UPS function during PHP (Wentzel, 2018).

Perturbation of proteasome function has diverse effects on cellular physiology, such as altering the levels of free ubiquitin and mono-ubiquitinated proteins, activating macroautophagy or upregulation of lysosomal enzyme levels. The observed phenotypes could thus be due to indirect effects of impaired proteasome function on synaptic physiology. Even if it is not possible to rule out this possibility, several lines of evidence argue against a major contribution of indirect effects. First, acute or prolonged proteasome perturbation does not affect release at synapses that express PHP. Second, genetic evidence is provided that proteasome perturbation-induced changes in release are blocked in two PHP mutants. Third, no major changes were detected in synaptic morphology or synaptic development upon prolonged proteasome perturbation. Fourth, interfering with proteasome function does not impair neurotransmitter release, but rather results in a net increase in release. Taken together, these data suggest that proteasome function opposes release by degrading proteins under baseline conditions, and that normal degradation of these proteins is required for PHP (Wentzel, 2018).

The genetic data imply that not all proteins required for PHP are regulated through UPS-dependent degradation under the experimental conditions (pharmacological proteasome perturbation for 15 min) used in this study, because release can be potentiated upon brief proteasome inhibition in most PHP mutants. This observation is consistent with a recent study demonstrating that the abundance of most synaptic proteins does not change after prolonged pharmacological proteasome perturbation in cultured mouse hippocampal neurons. Based on the current observation that PHP is blocked in cut-up mutants, which were recently shown to have a defect in proteasome trafficking, it is conceivable that proteasome mobility and/or recruitment are modulated during PHP (Wentzel, 2018).

Evidence is provided that proteasome perturbation and homeostatic signaling recruit EGTA-sensitive vesicles with a lower pr in addition to vesicles with higher pr. Previous work revealed that tightly-coupled, high-pr vesicles are required for PHP. PHP therefore likely involves vesicle pools with different pr . Homeostatic regulation of EGTA-sensitive, loosely-coupled vesicles depends on dysbindin, whereas tightly-coupled vesicles are controlled by RIM-binding protein. Together, these results imply that PHP involves two genetically separable populations of vesicles with different pr (Wentzel, 2018).

Vesicle pools with different pr and release kinetics have been observed at various synapses, and these pools might be differentially regulated during synaptic plasticity. This study provides evidence that dysbindin is required for the recruitment of EGTA-sensitive vesicles during PHP. It will be exciting to investigate the roles of other presynaptic proteins that have been implicated in the release of EGTA-sensitive vesicles, such as Tomosyn, in the context of proteasome degradation and PHP. Interestingly, a recent study at the mouse NMJ observed accelerated release kinetics of 'slow' synaptic vesicles during PHP. Thus, homeostatic potentiation of vesicles with lower pr /slower release kinetics may be an evolutionarily conserved mechanism (Wentzel, 2018).

Which mechanisms could potentiate the release of low-pr vesicles? This study revealed that presynaptic proteasome perturbation results in enhanced presynaptic Ca2+ influx, independent of major changes in Ca2+ buffering and/or extrusion. Therefore changes in presynaptic Ca2+ influx are considered as a possible mechanism underlying the increase in low-pr vesicle release. Proteasome perturbation also increased RRP size. Earlier work revealed that changes in presynaptic Ca2+ influx modulate release in part by altering apparent RRP size. The increase in RRP size or EGTA sensitivity upon proteasome inhibition may therefore be in part a secondary consequence of enhanced presynaptic Ca2+ influx. However, several observations, such as the increased amplitude of the fast recovery phase after pool depletion or the slowing of EPSC decay kinetics upon presynaptic proteasome perturbation, which are not seen after increasing [Ca2+]e, indicate that the increase in release is not caused by presynaptic Ca2+ influx alone. Together, these data imply that a combination of increased presynaptic Ca2+ influx and RRP size underlie the enhancement of release after proteasome or glutamate receptor perturbation. Which molecular mechanisms may link UPS function to the modulation of presynaptic Ca2+ influx or RRP size? Genetic data suggest that dysbindin functions independently of presynaptic Ca2+ influx. Interestingly, rim mutants were shown to have a defect in homeostatic RRP size modulation, but unchanged homeostatic control of presynaptic Ca2+ influx. It is therefore speculated that RIM and Dysbindin may be involved in proteasome-dependent RRP size regulation. How do these observations relate to mammalian synapses? At cultured hippocampal rat synapses, proteasome inhibition augments recycling vesicle pool size or prevents a decrease in RRP size induced by prolonged (4h) depolarization. Moreover, several studies at mammalian synapses suggest that UPS-dependent regulation of RIM abundance regulates neurotransmitter release during baseline synaptic transmission and synaptic plasticity. Finally, there is evidence that ubiquitination acutely regulates release on the minute time scale at cultured hippocampal rat synapses (Rinetti, 2010). Together, these studies suggest that rapid, UPS-dependent control of RRP size may be evolutionarily conserved. Future studies will further elucidate the molecular signaling pathways relating UPS function to neurotransmitter release during baseline synaptic transmission and homeostatic plasticity (Wentzel, 2018).

Functions of Dysbindin orthologs in other species

The proteome of BLOC-1 genetic defects identifies the Arp2/3 actin polymerization complex to function downstream of the schizophrenia susceptibility factor Dysbindin at the synapse
Proteome modifications downstream of monogenic or polygenic disorders have the potential to uncover novel molecular mechanisms participating in pathogenesis and/or extragenic modification of phenotypic expression. This idea was tested by determining the proteome sensitive to genetic defects in a locus encoding dysbindin (see Drosophila Dysbindin), a protein required for synapse biology and implicated in schizophrenia risk. Quantitative mass spectrometry was applied to identify proteins expressed in neuronal cells the abundance of which was altered after downregulation of the schizophrenia susceptibility factor dysbindin (Bloc1s8) or two other dysbindin-interacting polypeptides, which assemble into the octameric biogenesis of lysosome-related organelles complex 1 (BLOC-1). 491 proteins sensitive to dysbindin and BLOC-1 loss of function were found. Gene ontology of these 491 proteins singled out the actin cytoskeleton and the actin polymerization factor, the Arp2/3 complex (see Drosophila Arpc1), as top statistical molecular pathways contained within the BLOC-1-sensitive proteome. Subunits of the Arp2/3 complex were downregulated by BLOC-1 loss of function, thus affecting actin dynamics in early endosomes of BLOC-1-deficient cells. Furthermore, it was demonstrated that Arp2/3, dysbindin, and subunits of the BLOC-1 complex biochemically and genetically interact, modulating Drosophila melanogaster synapse morphology and homeostatic synaptic plasticity. These results indicate that ontologically prioritized proteomics identifies novel pathways that modify synaptic phenotypes associated with neurodevelopmental disorder gene defects (Gokhale, 2016).


Search PubMed for articles about Drosophila Dysbindin

Cai, Q., Lu, L., Tian, J. H., Zhu, Y. B., Qiao, H. and Sheng, Z. H. (2010). Snapin-regulated late endosomal transport is critical for efficient autophagy-lysosomal function in neurons. Neuron 68: 73-86. PubMed ID: 20920792

Chen, X. W., et al. (2008). DTNBP1, a schizophrenia susceptibility gene, affects kinetics of transmitter release. J. Cell Biol. 181(5): 791-801. PubMed ID: 18504299

Dickman, D. K. and Davis, G. W. (2009). The schizophrenia susceptibility gene dysbindin controls synaptic homeostasis. Science 326(5956): 1127-30. PubMed ID: 19965435

Dickman, D. K., Tong, A. and Davis, G. W. (2012). Snapin is critical for presynaptic homeostatic plasticity. J Neurosci 32: 8716-8724. PubMed ID: 22723711

Fei, E., et al. (2010). Nucleocytoplasmic shuttling of dysbindin-1, a schizophrenia-related protein, regulates synapsin I expression. J. Biol. Chem. 285(49): 38630-40. PubMed ID: 20921223

Gokhale, A., et al. (2015). The N-ethylmaleimide-sensitive factor and dysbindin interact to modulate synaptic plasticity. J Neurosci 35: 7643-7653. PubMed ID: 25972187

Gokhale, A., Hartwig, C., Freeman, A. H., Das, R., Zlatic, S. A., Vistein, R., Burch, A., Carrot, G., Lewis, A. F., Nelms, S., Dickman, D. K., Puthenveedu, M. A., Cox, D. N. and Faundez, V. (2016). The proteome of BLOC-1 genetic defects identifies the Arp2/3 actin polymerization complex to function downstream of the schizophrenia susceptibility factor Dysbindin at the synapse. J Neurosci 36(49): 12393-12411. PubMed ID: 27927957

Jiang, X., Litkowski, P. E., Taylor, A. A., Lin, Y., Snider, B. J. and Moulder, K. L. (2010). A role for the ubiquitin-proteasome system in activity-dependent presynaptic silencing. J Neurosci 30(5): 1798-1809. PubMed ID: 20130189

Larimore, J., et al. (2011). The schizophrenia susceptibility factor Dysbindin and its associated complex sort cargoes from cell bodies to the Synapse. Mol. Biol. Cell [Epub ahead of print]. PubMed ID: 21998198

Lazarevic, V., Schone, C., Heine, M., Gundelfinger, E. D. and Fejtova, A. (2011). Extensive remodeling of the presynaptic cytomatrix upon homeostatic adaptation to network activity silencing. J Neurosci 31(28): 10189-10200. PubMed ID: 21752995

Numakawa, T., et al. (2004). Evidence of novel neuronal functions of dysbindin, a susceptibility gene for schizophrenia. Hum. Mol. Genet. 13(21): 2699-708. PubMed ID: 15345706

Pan, P. Y., Tian, J. H. and Sheng, Z. H. (2009). Snapin facilitates the synchronization of synaptic vesicle fusion. Neuron 61: 412-424. PubMed ID: 19217378

Rinetti, G. V. and Schweizer, F. E. (2010). Ubiquitination acutely regulates presynaptic neurotransmitter release in mammalian neurons. J Neurosci 30(9): 3157-3166. PubMed ID: 20203175

Ross, C. A., et al. (2006). Neurobiology of schizophrenia. Neuron 52(1): 139-53. PubMed ID: 17015232

Shao, L., et al. (2011). Schizophrenia susceptibility gene dysbindin regulates glutamatergic and dopaminergic functions via distinctive mechanisms in Drosophila. Proc. Natl. Acad. Sci. 108(46): 18831-6. PubMed ID: 22049342

Speese, S. D., Trotta, N., Rodesch, C. K., Aravamudan, B. and Broadie, K. (2003). The ubiquitin proteasome system acutely regulates presynaptic protein turnover and synaptic efficacy. Curr Biol 13(11): 899-910. PubMed ID: 12781128

Talbot, K., et al. (2004). Dysbindin-1 is reduced in intrinsic, glutamatergic terminals of the hippocampal formation in schizophrenia. J. Clin. Invest. 113(9): 1353-63. PubMed ID: 15124027

Talbot, K., et al. (2006). Dysbindin-1 is a synaptic and microtubular protein that binds brain snapin. Hum. Mol. Genet. 15(20): 3041-54. PubMed ID: 16980328

Tian, J. H., Wu, Z. X., Unzicker, M., Lu, L., Cai, Q., Li, C., Schirra, C., Matti, U., Stevens, D., Deng, C., Rettig, J. and Sheng, Z. H. (2005). The role of Snapin in neurosecretion: snapin knock-out mice exhibit impaired calcium-dependent exocytosis of large dense-core vesicles in chromaffin cells. J Neurosci 25: 10546-10555. PubMed ID: 16280592

Weickert, C. S., et al. (2008). Reduced DTNBP1 (dysbindin-1) mRNA in the hippocampal formation of schizophrenia patients. Schizophr. Res. 98(1-3): 105-10. PubMed ID: 17961984

Wentzel, C., Delvendahl, I., Sydlik, S., Georgiev, O. and Muller, M. (2018). Dysbindin links presynaptic proteasome function to homeostatic recruitment of low release probability vesicles. Nat Commun 9(1): 267. PubMed ID: 29348419

Yao, I., Takagi, H., Ageta, H., Kahyo, T., Sato, S., Hatanaka, K., Fukuda, Y., Chiba, T., Morone, N., Yuasa, S., Inokuchi, K., Ohtsuka, T., Macgregor, G. R., Tanaka, K. and Setou, M. (2007). SCRAPPER-dependent ubiquitination of active zone protein RIM1 regulates synaptic vesicle release. Cell 130(5): 943-957. PubMed ID: 17803915

Biological Overview

date revised: 25 April 2018

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