Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Synapsin II

  • Ashley Bernardo
  • Shreya Prashar
  • Luke Molinaro
  • Ram Mishra
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101863

Synonyms

Historical Background

Synapsin II (SYN2) was identified in the late 1970s following studies that began searching for neuronal substrates for endogenous cyclic adenosine 3′:5′ monophosphate (cAMP)-dependent phosphorylation. cAMP had been suggested to mediate neurotransmitter regulation through synaptic membrane proteins and led to the discovery of several proteins including the family of synapsin proteins. Highly specific to nerve terminals, synapsins were among one of the first identified synaptic vesicle-associated protein families (De Camilli et al. 1990).

The first member identified in the synapsin family was synapsin I, initially named protein I, and described by Paul Greengard in 1972 as a primary synaptic membrane phosphorylation target by cAMP-dependent kinases (Johnson et al. 1972). Following the discovery of synapsin I, a second member of the synapsin family – protein III – later renamed synapsin II (SYN2) was identified in the late 1970s and found to constitute approximately 0.2% of total mammalian brain protein and 9% of vesicle proteins (De Camilli et al. 1990). Subsequently, the presence of two distinct SYN2 isoforms was identified and shown to display regional specific expression in the brain of rodents (Walaas et al. 1988). Follow-up research then focused on investigating the exact structure and function of this prominent neuronal phosphoprotein.

Currently, SYN2 is known to act in a phosphorylation-dependent manner, binding to the cytosolic surface of synaptic vesicle membranes as well as actin filaments (De Camilli et al. 1990). Further, studies identified SYN2’s role in the regulation of neurotransmitter release, neurite extension, synapse formation, and its involvement in later steps of the synaptic vesicle cycle, such as delivery, recycling, and exocytosis (De Camilli et al. 1990; Bykhovskaia 2011).

Protein Structure

The structure of SYN2 has been evolutionarily conserved across invertebrate and vertebrate species, such as Loligo pealeii (squid), Xenopus laevis (frog), Rattus norvegicus (rat), and Homo sapiens (humans) (Kao et al. 1999). In humans, the SYN2 gene consists of 187,673 bases mapped onto chromosome 3, at region p25. Upon translation, this region is converted into the 582 amino acid SYN2 protein, with a molecular mass of 62,847 Da. Alternative splicing of the SYN2 gene produces two splice variants, named SYN2a and SYN2b. These two isoforms have molecular weights of 74,000 daltons (Da) and 55,000 Da, respectively, and contain many similar structural domains (see https://www.ncbi.nlm.nih.gov/gene/6854 for further details).

The entire synapsin family contains several conserved domains at the NH2-terminus, while structural variations are localized to the COOH-terminus (Sudhof et al. 1989). Domains A, B, and C are conserved across all synapsins, while domain E is conserved only across the “a” isoforms of synapsins I, II, and III (Sudhof et al. 1989; De Camilli et al. 1990; Molinaro et al. 2015). Unique to SYN2 is domain G, which is present in both “a” and “b” isoforms and contains a fundamental actin binding site (Fig. 1).
Synapsin II, Fig. 1

Illustration demonstrating the various mammalian synapsin gene products. (a) Various domains are indicated as well as known phosphorylation sites and their kinases (color coded). (a) Domain E has been implicated in phospholipid vesicle clustering and dimerization (Modified Image courtesy of Molinaro et al. 2015. Used with author’s permission). (b) A schematic representation of synapsin domain “C” which has been identified as a major binding site for lipid membranes as well as actin filaments. Domain “C” is also responsible for dimerization of synapsins. Within this domain are amphipathic regions specific to high-affinity binding of both actin and phospholipids. This domain also contains multiple tyrosine phosphorylation sites for tyrosine kinase Src

Starting at the NH2-terminus, domain A consists of a short region containing a phosphorylation site (Ser10) for protein kinase A (PKA) and Ca2+/calmodulin-dependent protein kinase I (CaMK I) (De Camilli et al. 1990). Domain B is a subsequent linker region, rich in prolines, glutamines, alanines, and serines, which connects domains A and C (De Camilli et al. 1990). Within this linker region, two distinct binding sites have been mapped between amino acids 43–74 and 75–121. It is at these sites that SYN2 is able to bind to proteins on the membrane of synaptic vesicles (Thiel et al. 1990). Due to the high degree of homology within the NH2-terminus domains of synapsin I, it is very likely that domain B of SYN2 also contains phosphorylation sites for mitogen-activated protein kinase (MAPK) and Ca2+/calmodulin-dependent protein kinase II (CaMK II). (Sudhof et al. 1989). Following domain B is the most central and conserved domain of SYN2, domain C. This important domain is approximately 300 amino acids and accounts for more than half of the sequence length (Molinaro et al. 2015). Domain C has been identified as a major binding site for lipid membranes of synaptic vesicles and actin filaments as well as the site for synapsin dimerization (Cheetham et al. 2001). Conserved in this domain are amphipathic and hydrophobic regions essential for high-affinity binding to synaptic vesicles, penetration of their lipid bilayer, and a tyrosine phosphorylation site for tyrosine kinase Src (Cheetham et al. 2001).

Despite the synapsin family similarities in domains A–C, these phosphoprotein structures vary at the COOH-terminus. In SYN2, the major variation lies in the unique presence of domain G, a short proline-rich region that facilitates associations with the cytoskeleton via an actin binding site (De Camilli et al. 1990). Domain G is flanked by domains H and I, present in SYN2a and SYN2b isoforms, respectively. The final domain common to all synapsin “a” isoforms is domain E. This domain is responsible for maintaining the reserve pool by clustering synaptic vesicles and interacting with actin in the cytoskeleton to regulate exocytosis. Domain E is also responsible for mediating synapsin I and II binding, as well as synapsin dimerization (Bykhovskaia 2011). Each domain contains specific binding sites that relate to the multifunctional nature of SYN2.

Localization and Regulation

SYN2 is found in virtually all neuronal presynaptic terminals throughout the central and peripheral nervous systems (Sudhof et al. 1989; De Camilli et al. 1990). Despite being present in all nerve terminals, the relative expression of different synapsin isoforms varies between neuronal cell types. SYN2a and SYN2b are both found in mossy fiber terminals of hippocampal granule cells, while SYN2a is not observed in Purkinje cell axon terminals (Sudhof et al. 1989). The regional distribution of SYN2a and 2b is more consistent and follows a constant 1:2 ratio across various brain regions (Walaas et al. 1988). The exception to this rule is found within the olfactory bulb, where SYN2a concentrations are elevated in comparison to SYN2b, potentially in relation to the ongoing remodeling of synaptic contacts (Walaas et al. 1988).

This regional variation in SYN2 expression is regulated by a variety of transcription factors and the cellular environment. This region is rich in GC content and does not contain TATA and CAAT boxes (Petersohn et al. 1995). Thus, regulation is controlled by several other transcription factors with binding sites in this region. Binding sites for several transcription factors are present in the promoter region of SYN2, including zinc finger transcription factor early growth response factor (EGR-1), activation protein 2-alpha (AP-2α), and polyoma enhancer activator 3 (PEA-3) (Petersohn et al. 1995; Molinaro et al. 2015) (Fig. 2). EGR-1 is involved in the regulation of growth and differentiation pathways and considered a transcriptional activator for synapsin I. The levels of synapsin I expression are increased upon EGR-1 protein translocation to the nucleus and binding to the EGR-1 motif within the promoter region (Thiel et al. 1994). Similarly, the EGR-1 binding site identified on SYN2 has also been suggested to display a transcription modulating role (Petersohn et al. 1995). A binding site for PEA-3 is also within the promoter region of SYN2 and is influenced by serum promoters, tumor promoters, and gene products of several non-nuclear oncogenes (v-raf, v-src, Ha-ras, polyoma middle T-antigen) (Wasylyk et al. 1989). PEA-3 plays an important role in regulating SYN2 by activating transcription through the MAPK-PEA-3 pathway. Within this pathway, MAPK is activated through transduction cascades and translocated into the nucleus, where it binds to its substrate PEA-3, ultimately stimulating SYN2 expression (Petersohn et al. 1995).
Synapsin II, Fig. 2

Illustration of the various promoter regions of SYN2 and the proposed mechanism of dopaminergic regulation of SYN2. (a) Illustration of the promoter regions of synapsin I and II, respectively. Transcription factor binding sites have been indicated, showing their various positions in the promoter region; (b) proposed mechanism of dopaminergic regulation of SYN2. Evidence: (1) immunocytochemistry results indicate that ligand DARc binding results in changes to synapsin protein levels dependent on Rc subtype; (2) ligand binding causes changes to intercellular cAMP levels; (3) PKA inhibitors (5–24 amide trifluoroacetate salt, Rp-cAMPS) cause changes in SYN2 translation; (4) DA-D1 stimulation may cause AP-2 to bind to SYN2 promoter. SYN2 expression levels were inhibited when cells were treated with AP-2 ADONs. Subsequent treatment with DA-D1 or DA-D2 agonists showed to effect on SYN2 expression; and (5) synapsin 2 expression can be altered via upstream alteration at various points. Additional information: (1) EGR-1 levels are not affected by chronic treatment with DA-D1 or DA-D2 antagonists; (2) antisense deoxyoligonucleotides for AP-2 reduces SYN2 expression levels; and (3) antisense deoxyoligonucleotides for EGR-1 and PEA3 have no effect on the expression of SYN2. EGR-1, Early growth response factor-1; PKA, Protein kinase A; cAMP, Cyclic AMP; AP-2α, Activating protein 2-alpha (Image courtesy of Molinaro et al. 2015. Used with author’s permission)

The final transcription factor responsible for SYN2 regulation is AP-2α, a sequence-specific DNA-binding protein that activates transcription when interacting with enhancer elements (Petersohn et al. 1995). AP-2α binding sites are not found on synapsin I or III, making its regulation specific to SYN2. Two neighboring binding sites for AP-2α are found within the promoter region of SYN2. However, their close proximity likely diminishes the ability of both sites to be occupied simultaneously, with the more distal site being suggested as the more favorable AP-2α binding site (Petersohn et al. 1995). SYN2 levels are influenced by AP-2α and its upstream substrates, such as dopamine (DA). Dopamine indirectly regulates SYN2 expression via AP-2α, through dopamine receptor subtypes (DA-D1 and DA-D2), cAMP and PKA-dependent pathways. DA-D1 receptor stimulation or DA-D2 receptor inhibition increases SYN2 levels (Molinaro et al. 2015) (Fig. 2). Additionally, PKA activates AP-2α which mediates effects, by undergoing posttranslational modifications, such as sumoylation that facilitates changes in protein kinase C (PKC) and cAMP levels, in turn affecting the expression of SYN2 (Petersohn et al. 1995).

In addition to regulation by transcription factors, SYN2 expression levels are also influenced by methylation. The promoter region of SYN2 contains large GC-rich regions, also known as CpG islands, specifically in sequences surrounding transcription start sites. The addition of methyl groups to these CpG islands represses gene expression, and the lack of methylation increases SYN2 expression. CpG methylation mapping of postmortem samples from bipolar disorder and major depressive disorder patients identified DNA hypomethylation and significantly reduced SYN2 levels in patients compared to controls (Cruceanu et al. 2016). Thus, methylation also plays an important role in regulating SYN2 expression levels.

Function

Synapsin II has vital functional roles at multiple stages of the synaptic vesicle cycle, including clustering, reserve pool maintenance, delivery to the active zone, and synchronizing release of neurotransmitters. These functions are largely regulated by the dynamic balance between SYN2 phosphorylation and dephosphorylation occurring at domains C and E (De Camilli et al. 1990; Bykhovskaia 2011). As previously discussed, domains C and E are the major functional domains of SYN2 and the site of homo- and heterodimerization with other synapsins, which will be discussed later. Both of these domains function in an actin-dependent manner, while domain A has an actin-independent functional role in regulating neurotransmitter release (Bykhovskaia 2011). In addition to its performance in the synaptic vesicle cycle, SYN2 appears to influence synaptogenesis, synapse maintenance, synaptic plasticity, and synaptic vesicle membrane stabilization (Brenes et al. 2015).

Most synaptic vesicles are located at presynaptic nerve terminals in a cluster formation within the reserve pool. This occurs as a result of SYN2, largely SYN2a, cross-linkage between these synaptic vesicles and actin filaments of the cytoskeleton, thereby clustering the vesicles and maintaining the reserve pool (De Camilli et al. 1990). Following SYN2 phosphorylation, actin filaments dissociate and phosphorylation-dependent vesicle release occurs from the reserve pool. Upon stimulation, there is an increase in vesicle mobilization due to the influx of Ca2+ favoring the phosphorylated SYN2 state (Bykhovskaia 2011). The liberated vesicles then transition into the recycling pool and the readily releasable pool where SYN2 plays a major role in delivery and vesicle docking to the active zone. SYN2 demonstrates different vesicle pool regulatory roles in inhibitory and excitatory synapses. At excitatory synapses, SYN2 is largely responsible for the maintenance of the reserve pool. However, in GABAergic neurons, SYN2 plays a more substantial role in regulating the size of the readily releasable pool (Gitler et al. 2004). Delivery of synaptic vesicles to the active zone occurs in cooperation with Rab3a, which is a protein involved in targeting synaptic vesicles to the active zone. The Rab3a/synapsin complex then promotes liberation of vesicles from actin filaments and targets the vesicle to active zone machinery (Bykhovskaia 2011). Once docking has occurred, SYN2 then regulates exocytosis by synchronizing neurotransmitter release. The specific mechanism by which SYN2 mediates synchronous release is not fully understood (Fig. 3). However, it is hypothesized that coating vesicles with synapsin modifies membrane properties to promote accelerated fusion events in response to Ca2+ influx (Bykhovskaia 2011).
Synapsin II, Fig. 3

Illustration of various functional roles of SYN2 within the presynaptic neuron. Figure showcases various roles/stages which involve SYN2 with respect to controlled neurotransmitter release. Important stages have been indicated with a number and brief description. SYN2 is responsible for multiple functional roles at different stages of the synaptic vesicle cycle, including clustering, reserve pool maintenance, delivery to the active zone, and synchronizing release of neurotransmitters. (1) Vesicle synthesis and loading of neurotransmitters occurs at specific sites within a neuron. (2) Large numbers of synaptic vesicles are then clustered in a formation known as the reserve zone. Here SYN2a cross-links vesicles with actin filaments to maintain said reserves. Dimerized SYN2 molecules are also in high abundance at the reserve site. (3) Upon phosphorylation of SYN2, vesicles dissociate from actin filaments and begin mobilizing toward the active site. Vesicles transition to both the recycling pool and readily releasable pool at this point. Delivery to the active site occurs in cooperation with Rab3a. (4) Once at the active zone (site of vesicular release) SYN2 facilitates docking/binding to the phospholipid membrane prior to exocytotic release. Above image is simplified in many aspects as it does not cover all functions of SYN2 as it may play slightly different roles on the basis of neuron type/function (e.g., excitatory vs inhibitory)

SYN2 is also implicated in synaptogenesis, synapse maintenance, and plasticity. Knockdown studies of SYN2 demonstrate that a reduction in this phosphoprotein results in impaired cytoskeletal organization in early stages of nerve cell development. Aberrant cytoskeletal activity slows axonal outgrowth and diminishes neurite branching which in turn affects maintenance and functional activity of the synapse (Brenes et al. 2015). If reduced after axonal elongation but prior to synapse formation, then neurons do not form synapses, therefore elucidating the role of SYN2 in formation and maintenance of synapses. SYN2b may be responsible for nerve terminal formation, given that transfection with this isoform increased the number of nerve terminals and synaptic vesicles within each terminal (Brenes et al. 2015).

The final proposed function of SYN2 at presynaptic nerve terminals involves stabilization of synaptic vesicle membranes. When synapsins interact with the phospholipid bilayer, they induce a conformational change that increases alpha helices. This propagates the insertion of the N-terminal end into the hydrophobic core of the membrane. By inserting SYN2 into the membrane, this protein increases stabilization of the lipid bilayer and inhibits vesicle leakage and unregulated vesicle fusion. Additionally, synapsins have been suggested to be obligatory dimers on vesicle membranes, as dimerization promotes vesicle binding and clustering (Hosaka and Sudhof 1999). Dimerization occurs at domain C in all synapsin isoforms and is functionally regulated by activity-dependent Src phosphorylation. Homodimerization occurs in synapsin I, II, and III, and a weak heterodimer is formed between synapsin I and III. On the contrary SYN2 forms strong heterodimers with both synapsin I and synapsin III (Hosaka and Sudhof 1999).

Synapsin II and Disease

Dysfunction of synapsins has been hypothesized in various disease states due to their numerous roles in both development and proper functioning of synapses. Evidence suggests that this dysfunction may manifest in a variety of ways dependent on the isoform affected as well as the temporal span in which it is influenced. Some of the various diseases, which have been implicated with improper functioning of synapsins, include, but are not limited to, schizophrenia (SZ), Huntington’s disease (HD), Alzheimer’s disease (AD), autism spectrum disorder (ASD), epilepsy, Parkinson’s disease (PD), bipolar disorder (BD), and diabetes (Giovedi et al. 2014; Prasad et al. 2014; Molinaro et al. 2015).

Specifically, SYN2 dysfunction has been implicated in several disease states including SZ, AD, ASD, epilepsy, and BD. The role of SYN2 in the diseased state of SZ has been investigated in depth, allowing genetic susceptibility studies to reveal that the SYN2 gene is a region of vulnerability for possible SZ-related mutations (Molinaro et al. 2015). SYN2 has also been found to play an integral role in neuronal nitric oxide synthase (nNOS) localization through its relationship with CAPON. nNOS has functional roles in neurotransmitter release and neuronal process outgrowth and has been implicated in SZ and BD. The CAPON gene has also since been identified as a gene candidate susceptible in the pathogenesis of SZ (Zheng et al. 2005). Accumulating evidence implicates SYN2 in the pathophysiology of SZ including decreased SYN2 levels within the dorsolateral prefrontal cortex of schizophrenic patients (Molinaro et al. 2015). Consolidating this data are SYN2 knockdown experiments producing schizophrenic-like behaviors in rats, reflecting several SZ symptom domains (Molinaro et al. 2015). Knockdown of SYN2 has been established to produce reduced signaling in different neurotransmitter systems including inhibitory GABA neurons as well as excitatory glutamatergic neurons. Modified excitatory and inhibitory signaling has been implicated in SZ symptoms and is the origin of several hypotheses attempting to explain the cause of the disorder (Molinaro et al. 2015). Genetic studies have also revealed a potential role for SYN2 in the etiology of BD (Tan et al. 2014). Both illnesses present with a spectrum of symptoms ranging in severity across individuals, and there remains a great deal of overlap between the clinical manifestation of BD and SZ. These commonalities between BD and SZ suggest potential similarities in their pathophysiology, including SYN2 dysfunction.

Preclinical work investigating SYN2 has also shed light on its roles in neurological disease states such as epilepsy and AD. Phenotypes indicative of both epilepsy and AD are produced in complete knockdown/knockout SYN2 rodent models (Gitler et al. 2004), and genetic studies have complemented these results by describing SYN2 gene polymorphisms as risk factors for epilepsy (Prasad et al. 2014). Several mutations in the SYN2 gene have also been implicated in the development of ASD (Giovedi et al. 2014), and knockdown/knockout studies of SYN2 demonstrate several autism-related behaviors such as impairments in social and repetitive behaviors (Giovedi et al. 2014). Given the breadth of SYN2 involvement in synaptogenesis, synapse maintenance, vesicle cycle coordination, and neurotransmission regulation, the dysfunction of this phosphoprotein at any stage in life can contribute to a vast number of neurological disease states (Fig. 4).
Synapsin II, Fig. 4

provides a comprehensive visual of the current research available with regard to links that have been established between SYN2 and several neurological disorders. The ✔ indicates research areas that have one or more studies relating SYN2 to different levels of each disorder. The ? reveals research areas that have not been explored or identified in published literature. In the animal and cellular model systems, developmental studies refer to research that has been conducted to determine changes in SYN2 levels during development, ultimately leading to the onset of disease. Behavior studies refer to knockdown and knockout studies where a disruption in normal SYN2 structure, regulation, or function led to abnormal behaviors, while biochemical studies include wet-lab experiments checking for gene and/or protein expression to establish the role of SYN2 in diseases. The studies looking at effect of treatment aim to determine the efficacy of current clinical treatments at preventing and/or rescuing SYN2 levels in these disease models. As for the clinical aspect, SYN2 gene mutation studies looked at populations where mutations in SYN2 gene were correlated with the listed diseases. Clinical developmental research studies utilized postmortem samples to analyze levels of SYN2 at different stages of development, in order to determine critical developmental periods where changes in SYN2 levels occurred. The biochemical clinical studies examined postmortem patient samples to determine SYN2 levels. The clinical studies looking at the effect of treatment aim to determine the efficacy of current clinical treatments at preventing and/or rescuing SYN2 levels in patients. It should be noted that ✔ only indicates that there has been research suggesting this link; however further research is required in many, if not all, areas to develop a more complete understanding. As the table shows, SZ has been one of the most studied neurological disorders linked to SYN2 dysfunction. Minimal research has been conducted regarding the role of SYN2 in diseases such as AD and BD, despite several genetic and biochemical implications for aberrant SYN2 functioning. In vivo and in vitro models of these diseases have provided large amounts of valuable data. Clinical research is limited by many factors such as ethics, confounding factors, and limited sample availability, therefore making human research very difficult

Summary

The synapsin family of phosphoproteins was first described in the 1970s via research investigating the roles of cAMP. First identified as “protein III,” SYN2 has since been determined to exist in two isoforms (A and B) and constitutes 0.2% of total mammalian brain protein and approximately 9% of total vesicle proteins. Structurally, the synapsin family consists of multiple evolutionarily conserved domains which may vary slightly depending on isoforms. Domain C plays an integral role as it has been identified as a major binding site for lipid membranes, thus showcasing its importance in the synaptic vesicle cycle. Specific to SYN2, domain G is a proline-rich region which may facilitate the binding of synapsin to cytoskeletal elements such as actin.

Regulation of SYN2 expression is achieved by a variety of cellular mechanisms and transcription factors. The promoter region for SYN2 has been found to include binding sites for EGR-1, PEA-3, as well as AP-2α. Individual promoter sites may be indicative of the varying functional roles of SYN2, such as EGR-1 involvement in growth and differentiation. SYN2 is the only phosphoprotein in the synapsin family with known AP-2α binding sites. These binding sites may be responsible for the dopaminergic control of SYN2 as discussed previously. In addition to regulation by transcription factors, SYN2 expression levels can also be influenced by methylation events.

Functionally, SYN2 plays a wide variety of roles in both developing and mature neuronal tissues. Often considered its most important function, SYN2 regulates vesicular release in a phosphorylation-dependent manner. This is accomplished via interaction between SYN2, cytoskeletal elements, and phospholipid membranes. Studies have also determined a developmental role of SYN2 with respect to synaptogenesis, synapse maintenance, as well as plasticity. These developmental functions are often attributed to the SYN2b isoform. In this manner, SYN2 also acts as a phospholipid membrane stabilizer, reducing both vesicular leakage and unintentional vesicle fusion. SYN2 was also found to play roles in the synaptic vesicle cycle (delivery, release, recycling) as well as development (neurite extension and synapse formation).

Due to the variety of aforementioned functions, SYN2 may play a large role in health and disease. Various studies have shown SYN2 function/dysfunction to be indicative of certain disease states including (but not limited to) SZ, PD, AD, ASD, BD, and even HD. Given the breadth of functions SYN2 is involved in, including synaptogenesis, synapse maintenance, vesicle cycle coordination, and regulating neurotransmission, the dysfunction of this phosphoprotein at any stage in life can contribute to a number of disease states (Fig. 5).
Synapsin II, Fig. 5

Overview image of all major points made with respect to SYN2. Image provides both a simplified understanding of function and regulation of SYN2, as well as evidence suggesting its involvement in neuropsychiatric disease (Image has been modified from a previously published figure, used with author’s permission)

Various challenges surround research involving SYN2. As discussed above, SYN2 is involved in numerous functions at various points in development and maintenance. Due to the expansive range of functions, determining which are critical to various disease/psychological states can be difficult. In addition, clinically relevant tissues are often difficult to obtain and are often present in the form of postmortem tissues. Unfortunately, these patients have often been treated with various drugs or a combination of drugs, which is an undeniable confounding factor that reduces the significance of these samples.

Future studies should be conducted to specifically determine the full quaternary structure of SYN2. These studies would provide valuable information pertaining to functions and specific details necessary for a full understanding of this particular synapsin. This is important, as much of our current knowledge is inferred from studies of synapsin I due to their structural similarities. With respect to SYN2, future studies should be directed toward the investigation of the temporal importance of expression. Due to the number of varying functions, it is important to determine those most integral to health and disease. Studies which translate this information to a clinical level will provide vital insight to the role of SYN2 in neuropsychological disorders and promote SYN2 as a therapeutic target for these diseases. Furthermore, this research can lead to the discovery of novel treatment options targeting the underlying pathophysiology of these diseases instead of symptom management.

Notes

Acknowledgments

The work described in this review was supported by the Canadian Institute of Health Research (CIHR).

References

  1. Brenes O, Giachello CNG, Corradi AM, Ghirardi M, Montarolo PG. Synapsin knockdown is associated with decreased neurite outgrowth, functional synaptogenesis impairment and fast high-frequency neurotransmitter release. J Neurosci Res. 2015;93(10):1492–506. doi:10.1002/jnr.23624.PubMedCrossRefGoogle Scholar
  2. Bykhovskaia M. Synapsin regulation of vesicle organization and functional pools. Semin Cell Dev Biol. 2011;22(4):387–92. doi:10.1016/j.semcdb.2011.07.003.PubMedCrossRefGoogle Scholar
  3. Cheetham JJ, Hilfiker S, Benfenati F, Weber T, Greengard P, Czernik AJ. Identification of synapsin I peptides that insert into lipid membrane. Biochem J. 2001;354(1):57–66. doi:10.1042/bj3540057.PubMedPubMedCentralCrossRefGoogle Scholar
  4. Cruceanu C, Kutsarova E, Chen ES, Checknita DR, Nagy C, Lopez JP, Alda M, Rouleau GA, Turecki G. DNA hypomethylation of synapsin II CpG islands associates with increased gene expression in bipolar disorder and major depression. BMC Psychiatry. 2016;16:286. doi:10.1186/s12888-016-0989-0.PubMedPubMedCentralCrossRefGoogle Scholar
  5. De Camilli P, Benfenati F, Valtorta F, Greengard P. The synapsins. Annu Rev Cell Biol. 1990;6:433–60. doi:10.1146/annurev.cb.06.110190.002245.PubMedCrossRefGoogle Scholar
  6. Giovedi S, Corradi A, Fassio A, Benfenati F. Involvement of synaptic genes in the pathogenesis of autism spectrum disorders: the case of synapsins. Front Pediatr. 2014;2(94):1–8. doi:10.3389/fped.2014.00094.Google Scholar
  7. Gitler D, Takagashi Y, Feng J, Ren Y, Rodriguiz RM, Wetsel WC, Greengard P. Augustine GJ. Different presynaptic roles of synapsins at excitatory and inhibitory synapses. J Neurosci. 2004;24(50):11368–80. http://dx.doi.org/10.1523/JNEUROSCI.3795-04.2004.PubMedCrossRefGoogle Scholar
  8. Hosaka M, Sudhof TC. Homo- and heterodimerization of synapsins. J Biol Chem. 1999;274(24):16747–53. doi:10.1074/jbc.274.24.16747.PubMedCrossRefGoogle Scholar
  9. Johnson EM, Ueda T, Maeno H, Greengard P. Adenosine 3′, 5-Monophosphate-dependent phosphorylation of a specific protein in synaptic membrane fractions from rat cerebrum. J Biol Chem. 1972;247(17):5650–2.PubMedGoogle Scholar
  10. Kao H, Porton B, Hilfiker S, Stefani G, Pieribone VA, DeSalle R, Greengard P. Molecular evolution of the synapsin gene family. J Exp Zool. 1999;285:360–77. doi:10.1002/(SICI)1097-010X(19991215)285:4<360::AID-JEZ4>3.0.CO;2-3.PubMedCrossRefGoogle Scholar
  11. Molinaro L, Hui P, Tan M, Mishra RK. Role of presynaptic phosphoprotein synapsin II in schizophrenia. World J Psychiatry. 2015;5(3):260–72. doi:10.5498/wjp.v5.i3.260.PubMedPubMedCentralGoogle Scholar
  12. Petersohn D, Schoch S, Brinkmann DR, Thiel G. The human synapsin II gene promoter: Possible role for the transcription factors ZIF268/EGR-1, polyoma enhancer activator 3, and AP2. J Biol Chem. 1995;270(41):24361–9. doi:10.1074/jbc.270.41.24361.PubMedCrossRefGoogle Scholar
  13. Prasad DK, Shaheen U, Satyanarayana U, Prabha TS, Jyothy A, Munshi A. Association of GABRA6 1519 T > C (rs3219151) and synapsin II (rs37733634) gene polymorphisms with development of idiopathic generalized epilepsy. Epilepsy Res. 2014;108(8):1267–73. doi:10.1016/j.eplepsyres.2014.07.001.PubMedCrossRefGoogle Scholar
  14. Sudhof TC, Czernik AJ, Kao HT, Takei K, Johnston PA, Horiuchi A, Kanazir SD, Wagner MA, Perin MS, De Camilli P, et al. Synapsins: mosaics of shared and individual domains in a family of synaptic vesicle phosphoproteins. Science. 1989;245(4925):1474–80. doi:10.1126/science.2506642.PubMedCrossRefGoogle Scholar
  15. Tan M, Dyck BA, Gabriele J, Daya R, Thomas N, Sookram C, Basu D, Ferro MA, Mishra RK. Synapsin II gene expression in the dorsolateral prefrontal cortex of brain specimens from patients with schizophrenia and bipolar disorder: Effect of lifetime intake of antipsychotic drugs. Pharm J. 2014;14(1):63–9. doi:10.1038/tpj.2013.6.Google Scholar
  16. Thiel G, Schoch S, Petersohn D. Regulation of synapsin I gene expression by zinc finger transcription factor zif268/egr-1. J Biochem. 1994;269(21):15294–301.Google Scholar
  17. Thiel G, Sudhof TC, Greengard P. SYN2. Mapping of a domain in the NH2-terminal region which binds to small synaptic vesicles. J Biol Chem. 1990;265(27):16527–33.PubMedGoogle Scholar
  18. Walaas SI, Browning MD, Greengard P. Synapsin Ia, synapsin Ib, protein IIIa, and protein IIIb, four related synaptic vesicle-associated phosphoproteins, share regional and cellular localization in rat brain. J Neurochem. 1988;51(4):1214–20.PubMedCrossRefGoogle Scholar
  19. Wasylyk C, Flores P, Gutman A, Wakylyk B. PEA-3 is a nuclear target for transcription activation by non-nuclear oncogenes. EMBO J. 1989;8(11):3371–8.PubMedPubMedCentralGoogle Scholar
  20. Zheng Y, Li H, Qin W, Chen W, Duan Y, Xiao Y, Li C, Zhang J, Li X, Feng G, et al. Association of the carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase gene with schizophrenia in the Chinese Han population. Biochem Biophys Res Commun. 2005;328:809–15.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Ashley Bernardo
    • 1
  • Shreya Prashar
    • 1
  • Luke Molinaro
    • 1
  • Ram Mishra
    • 2
  1. 1.McMaster Integrative Neuroscience Discovery and StudyMcMaster UniversityHamiltonCanada
  2. 2.Psychiatry and Behavioural NeuroscienceMcMaster UniversityHamiltonCanada