dysbindin: Biological Overview | References
Gene name - dysbindin
Cytological map position - 75E2-75E2
Function - signaling
Symbol - dysb
FlyBase ID: FBgn0036819
Genetic map position - chr3L:18,860,877-18,862,321
Classification - coiled-coil-containing protein
Cellular location - cytoplasmic
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.
|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).
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).
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).
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).
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).
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., 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
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
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
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
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
date revised: 20 February 2017
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