• synapsins
• synaptic vesicle clustering
• synaptic vesicle trafficking
• tetramerization

• MOH-000225-00 Ministry of Health-Singapore
• Temasek Life sciences Laboratory

• alpha-synuclein
• cell biology
• mouse
• neuroscience
• presynaptic
• synapsin
• synaptic terminals
• synaptic transmission
• synaptic vesicles

• Animals
• Humans
• Mice
• alpha-Synuclein/metabolism
• alpha-Synuclein/genetics
• alpha-Synuclein/chemistry
• Cells, Cultured
• Hippocampus/metabolism
• Neurons/metabolism
• Protein Binding
• Protein Domains
• Synapses/metabolism
• Synapsins/metabolism
• Synapsins/genetics
• Synaptic Vesicles/metabolism

• P30 NS047101 NINDS NIH HHS
• R01 NS111978 NINDS NIH HHS
• P30NS047101 NINDS NIH HHS
• R01NS111978 NINDS NIH HHS
• United States-Israel Binational Science Foundation
• Israel Science Foundation
• Bergida Endowment on Parkinson's Disease Research
• National Institute of Neurological Disorders and Stroke
• Farmer Family Foundation
• Aligning Science Across Parkinson’s
• American Parkinson Disease Association
• Parkinson's Foundation

• vesicle trafficking
• synaptic vesicle exocytosis
• imaging

• Synaptic Vesicles/physiology
• Synapsins/genetics
• Synapses
• Synaptic Transmission/physiology
• Neurons/physiology
• Presynaptic Terminals

• R21 AG080435 NIA NIH HHS
• Department of Education and Training | ARC | Centre of Excellence for Integrative Brain Function, Australian Research Council (ARC Centre of Excellence for Integrative Brain Function)
• ARC Linkage Infrastructure, Equipment, and Facilities grant (LE130100078) National Health and Medical Research Council (NHMRC) Fellowship (1155794)
• European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No 882673) and ANR AstroXcite.

• pHluorin
• synapses
• synapsin
• vesicle pools
• α-synuclein

• P30 NS047101 NINDS NIH HHS
• R01 NS111978 NINDS NIH HHS

• membrane trafficking
• biophysical chemistry
• molecular neuroscience

• Animals
• Synaptic Vesicles/metabolism
• Synapsins/genetics
• Synapsins/metabolism
• Synapses/metabolism
• Synaptic Transmission/physiology
• Animals, Genetically Modified

• Deutsche Forschungsgemeinschaft (German Research Foundation)

• CP: Neuroscience
• liquid-liquid phase separation
• synapsins
• synaptic vesicle trafficking, oligomerization

• Synapsins
• Synapses
• Cluster Analysis
• Glutamic Acid
• gamma-Aminobutyric Acid

• ACh release
• Electrical stimulation
• Neuromuscular junction
• Neurotransmission
• PKA subunits
• SNAP-25
• Synapse
• Synapsin-1
• Synaptic activity

• Synapsins
• neurodevelopment
• neurological disorders
• neurotransmission
• post-translational modifications
• psychiatric disorders

In presynaptic terminals, synaptic vesicles (SVs) are found in a discrete cluster that includes a reserve pool that is mobilized during synaptic activity. Synapsins serve as a key protein for maintaining SVs within this reserve pool, but the mechanism that allows synapsins to do this is unclear. This mechanism is likely to involve synapsins either cross-linking SVs, thereby anchoring SVs to each other, or creating a liquid phase that allows SVs to float within a synapsin droplet. Here, we summarize what is known about the role of synapsins in clustering of SVs and evaluate experimental evidence supporting these two models.

• neurotransmitter release
• presynaptic terminals
• synapsins
• synaptic vesicle trafficking

• Animals
• Exocytosis
• Humans
• Models, Neurological
• Presynaptic Terminals/metabolism
• Protein Binding
• Protein Transport
• Synapsins/metabolism
• Synaptic Transmission
• Synaptic Vesicles/metabolism

The Synaptotagmin (SYT) family of proteins play key roles in regulating membrane trafficking at neuronal synapses. Using both Ca²⁺-dependent and Ca²⁺-independent interactions, several SYT isoforms participate in synchronous and asynchronous fusion of synaptic vesicles (SVs) while preventing spontaneous release that occurs in the absence of stimulation. Changes in the function or abundance of the SYT1 and SYT7 isoforms alter the number and route by which SVs fuse at nerve terminals. Several SYT family members also regulate trafficking of other subcellular organelles at synapses, including dense core vesicles (DCV), exosomes, and postsynaptic vesicles. Although SYTs are linked to trafficking of multiple classes of synaptic membrane compartments, how and when they interact with lipids, the SNARE machinery and other release effectors are still being elucidated. Given mutations in the SYT family cause disorders in both the central and peripheral nervous system in humans, ongoing efforts are defining how these proteins regulate vesicle trafficking within distinct neuronal compartments. Here, we review the Drosophila SYT family and examine their role in synaptic communication. Studies in this invertebrate model have revealed key similarities and several differences with the predicted activity of their mammalian counterparts. In addition, we highlight the remaining areas of uncertainty in the field and describe outstanding questions on how the SYT family regulates membrane trafficking at nerve terminals.

• Drosophila
• Exocytosis
• Neurotransmitter release
• Synapse
• Synaptic vesicle
• Synaptotagmin

• machine learning
• multiplexed imaging
• synaptic plasticity
• synaptic scaling

The number of neurotransmitter-filled vesicles released into the synaptic cleft with each action potential dictates the reliability of synaptic transmission. Variability of this fundamental property provides diversity of synaptic function across brain regions, but the source of this variability is unclear. The prevailing view is that release of a single (univesicular release, UVR) or multiple vesicles (multivesicular release, MVR) reflects variability in vesicle release probability, a notion that is well-supported by the calcium-dependence of release mode. However, using mouse brain slices, we now demonstrate that the number of vesicles released is regulated by the size of the readily-releasable pool, upstream of vesicle release probability. Our results point to a model wherein protein kinase A and its vesicle-associated target, synapsin, dynamically control release site occupancy to dictate the number of vesicles released without altering release probability. Together these findings define molecular mechanisms that control MVR and functional diversity of synaptic signaling.

Our nervous system allows us to rapidly sense and respond to the world around us via cells called neurons that relay electrical signals around the brain and body. When an electrical impulse travelling along one neuron reaches a junction – called a synapse – with a neighboring neuron, it stimulates small containers known as vesicles from the first cell to release their contents into the synapse. These contents then travel across to the neighboring cell and may generate a new electrical impulse.

The number of vesicles at a synapse that are ready to be released varies from one to ten. The more vesicles the neuron releases, the more likely the second cell will produce an electrical signal of its own. However, not all electrical signals reaching a synapse stimulate vesicles to be released and some signals only release a single vesicle.

What determines how many vesicles are released by a single electrical signal? Some vesicles have a higher likelihood of being released than others, but this “eagerness” does not always predict how many vesicles an individual synapse will actually discharge. Now, Vaden et al. have used brain tissue from mice to test an alternative possibility: the simple idea that the number of vesicles available at the synapse affects how many vesicles are released without altering their eagerness for release.

Vaden et al. found that activating an enzyme called protein kinase A increased the number of vesicles released from synapses without changing how likely individual vesicles were to be released. Inhibiting protein kinase A also did not change individual vesicle’s eagerness to be released, but did decrease the number of vesicles that were discharged. Further experiments found that protein kinase A modifies a molecule on the surface of vesicles, known as synapsin, which controls the number of vesicles that are available for release.

These findings show that the number of vesicles released at a synapse is controlled by two independently regulated parameters: the number of vesicles that are available, as well as how eager individual vesicles are to be released. The ability of neurons to communicate with each other is disrupted in autism spectrum disorders, Alzheimer’s disease and many other diseases. Learning how neurons communicate in healthy brains will help us understand what happens in the neurons of individuals with these conditions.

• RRP
• cerebellum
• mouse
• neuroscience
• synaptic transmission
• vesicle release

• Neurite
• Synapse
• Synaptic vesicle
• sEPSC
• sIPSC

We used genetic and pharmacological approaches to identify the signaling pathways involved in augmentation and potentiation, two forms of activity dependent, short-term synaptic plasticity that enhance neurotransmitter release. Trains of presynaptic action potentials produced a robust increase in the frequency of miniature excitatory postsynaptic currents (mEPSCs). Following the end of the stimulus, mEPSC frequency followed a bi-exponential decay back to basal levels. The time constants of decay identified these two exponential components as the decay of augmentation and potentiation, respectively. Augmentation increased mEPSC frequency by 9.3-fold, while potentiation increased mEPSC frequency by 2.4-fold. In synapsin triple-knockout (TKO) neurons, augmentation was reduced by 83% and potentiation was reduced by 74%, suggesting that synapsins are key signaling elements in both forms of plasticity. To examine the synapsin isoforms involved, we expressed individual synapsin isoforms in TKO neurons. While synapsin IIIa rescued both augmentation and potentiation, none of the other synapsin isoforms produced statistically significant amounts of rescue. To determine the involvement of protein kinases in these two forms of short-term plasticity, we examined the effects of inhibitors of protein kinases A (PKA) and C (PKC). While inhibition of PKC had little effect, PKA inhibition reduced augmentation by 76% and potentiation by 60%. Further, elevation of intracellular cAMP concentration, by either forskolin or IBMX, greatly increased mEPSC frequency and occluded the amount of augmentation and potentiation evoked by electrical stimulation. Finally, mutating a PKA phosphorylation site to non-phosphorylatable alanine largely abolished the ability of synapsin IIIa to rescue both augmentation and potentiation. Together, these results indicate that PKA activation is required for both augmentation and potentiation of spontaneous neurotransmitter release and that PKA-mediated phosphorylation of synapsin IIIa underlies both forms of presynaptic short-term plasticity.

• PKA
• neurotransmitter release
• post-tetanic potentiation
• synapsins
• synaptic plasticity

• C. elegans
• Synapse
• Synaptic proteins
• Synaptic vesicles
• Synaptogenesis

• Animals
• Caenorhabditis elegans/cytology
• Caenorhabditis elegans Proteins/metabolism
• Neurons/physiology
• Presynaptic Terminals/physiology
• Synapses/metabolism
• Synaptic Transmission

• GABA
• exocytosis
• hippocampus
• interneurons
• synapsin
• synaptic vesicle trafficking

• CCK
• GABA
• PV
• epilepsy
• hippocampus
• inhibitory

• neurotransmitter release
• presynaptic terminals
• synapsins
• synaptic vesicles
• vesicle trafficking

• Humans
• Neurotransmitter Agents/metabolism
• Phosphorylation/physiology
• Presynaptic Terminals/metabolism
• Protein Isoforms/metabolism
• Protein Transport/physiology
• Synapsins/metabolism
• Synaptic Vesicles/metabolism

Synapsin II is a member of the neuronal phosphoprotein family. These phosphoproteins are evolutionarily conserved across many organisms and are important in a variety of synaptic functions, including synaptogenesis and the regulation of neurotransmitter release. A number of genome-wide scans, meta-analyses, and genetic susceptibility studies have implicated the synapsin II gene (3p25) in the etiology of schizophrenia (SZ) and other psychiatric disorders. Further studies have found a reduction of synapsin II mRNA and protein in the prefrontal cortex in post-mortem samples from schizophrenic patients. Disruptions in the expression of this gene may cause synaptic dysfunction, which can result in neurotransmitter imbalances, likely contributing to the pathogenesis of SZ. SZ is a costly, debilitating psychiatric illness affecting approximately 1.1% of the world’s population, amounting to 51 million people today. The disorder is characterized by positive (hallucinations, paranoia), negative (social withdrawal, lack of motivation), and cognitive (memory impairments, attention deficits) symptoms. This review provides a comprehensive summary of the structure, function, and involvement of the synapsin family, specifically synapsin II, in the pathophysiology of SZ and possible target for therapeutic intervention/implications.

• Synapsin II
• Schizophrenia
• Dopamine
• Glutamate
• Neuropsychiatry
• Antipsychotic drugs

• AC1
• Calcium
• Synapsin
• cAMP
• α7 nAChRs

• ATP
• phosphorylation
• short-term plasticity
• synapsin
• synaptic vesicle
• vesicle pools

• ATP binding
• inhibitory transmission
• molecular dynamics simulations
• synapsins
• synaptic ultrastructure
• synaptic vesicles

• Clathrin
• Deamidation
• Synapsin1
• Synaptic failure
• Vascular dementia
• α/β-tubulins

• autism
• human mutations
• knockout mice
• social behavior
• synaptic transmission
• synaptic vesicles
• synaptopathies

• active zone
• short-term depression
• synapse
• synaptic transmission
• vesicle cluster

• Animals
• Blotting, Northern
• Cells, Cultured
• Codon, Nonsense
• Epilepsy/genetics
• Epilepsy/metabolism
• Female
• Gene Expression
• Genetic Diseases, X-Linked/genetics
• Genetic Diseases, X-Linked/metabolism
• HeLa Cells
• Hippocampus/cytology
• Hippocampus/metabolism
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Microscopy, Fluorescence
• Microtubule-Associated Proteins/metabolism
• Neurons/metabolism
• Nonsense Mediated mRNA Decay
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Rats
• Rats, Sprague-Dawley
• Synapsins/genetics
• Synapsins/metabolism

• GGP09134 Telethon

In the central nervous system, most synapses show a fast mode of neurotransmitter release known as synchronous release followed by a phase of asynchronous release, which extends over tens of milliseconds to seconds. Synapsin II (SYN2) is a member of the multigene synapsin family (SYN1/2/3) of synaptic vesicle phosphoproteins that modulate synaptic transmission and plasticity, and are mutated in epileptic patients. Here we report that inhibitory synapses of the dentate gyrus of Syn II knockout mice display an upregulation of synchronous neurotransmitter release and a concomitant loss of delayed asynchronous release. Syn II promotes γ-aminobutyric acid asynchronous release in a Ca²⁺-dependent manner by a functional interaction with presynaptic Ca²⁺ channels, revealing a new role in synaptic transmission for synapsins.

The arrival of action potentials at nerve terminals often leads to synchronous neurotransmitter release. Medrihan and colleagues use electrophysiology on mouse hippocampal neurons to show that the vesicle protein Synapsin II promotes GABAergic asynchronous release by interacting with calcium channels.

In mammalian brain, the cellular and molecular events occurring in both synapse formation and plasticity are difficult to study due to the large number of factors involved in these processes and because the contribution of each component is not well defined. Invertebrates, such as Drosophila, Aplysia, Helix, Lymnaea, and Helisoma, have proven to be useful models for studying synaptic assembly and elementary forms of learning. Simple nervous system, cellular accessibility, and genetic simplicity are some examples of the invertebrate advantages that allowed to improve our knowledge about evolutionary neuronal conserved mechanisms. In this paper, we present an overview of progresses that elucidates cellular and molecular mechanisms underlying synaptogenesis and synapse plasticity in invertebrate varicosities and their validation in vertebrates. In particular, the role of invertebrate synapsin in the formation of presynaptic terminals and the cell-to-cell interactions that induce specific structural and functional changes in their respective targets will be analyzed.

• Animals
• Humans
• Nerve Endings/metabolism
• Phosphorylation
• Synapses/metabolism
• Synapsins/metabolism
• Synaptic Vesicles/metabolism

• R01 MH061059 NIMH NIH HHS
• U54 NS039408 NINDS NIH HHS

Repeated release of transmitter from presynaptic elements depends on stimulus-induced Ca²⁺ influx together with recruitment and priming of synaptic vesicles from different vesicle pools. We have compared three different manipulations of synaptic strength, all of which are known to increase short-term synaptic efficacy through presynaptic mechanisms, in the glutamatergic CA3-to-CA1 stratum radiatum synapse in the mouse hippocampal slice preparation. Synaptic responses elicited from the readily releasable vesicle pool during low-frequency synaptic activation (0.1 Hz) were significantly enhanced by both the adenylate cyclase activator forskolin, the priming activator β-phorbol-12,13-dibutyrate (PDBu) and 4 mM [Ca²⁺]_o′ whereas during 20 Hz stimulation, the same manipulations reduced the time needed to reach the peak and increased the magnitude of the resulting frequency facilitation. In contrast, paired-pulse facilitations were unchanged in the presence of forskolin, decreased by 4 mM [Ca²⁺]_o and essentially abolished by PDBu. The subsequent delayed response enhancement (DRE) responses, elicited during continuous 20 Hz stimulations and mediated by recruited vesicles, were enhanced by forskolin, essentially unchanged by PDBu and slightly decreased by 4 mM [Ca²⁺]_o· Similar experiments done on slices devoid of the vesicle-associated synapsin I and II proteins indicated that synapsin I/II-induced enhancements of vesicle recruitment were restricted to Ca²⁺-induced frequency facilitations and forskolin-induced enhancements of the early DRE phase, whereas the proteins had minor effects during PDBu-treatment and represented constraints on late Ca²⁺-induced responses. The data indicate that in these glutamatergic synapses, the comparable enhancements of single synaptic responses induced by these biochemical mechanisms can be transformed during prolonged synaptic stimulation into highly distinct short-term plasticity patterns, which are partly dependent on synapsins I/II.

• calcium
• forskolin
• glutamate
• phorbol ester
• presynaptic plasticity
• synapsin

• gene regulation
• neurobiology
• neurochemistry
• nuclear translocation
• nuclear transport
• protein translocation
• dysbindin
• sandy mice
• schizophrenia
• synapsin i

• Active Transport, Cell Nucleus/drug effects
• Active Transport, Cell Nucleus/genetics
• Animals
• Antibiotics, Antineoplastic/pharmacology
• Brain/metabolism
• Carrier Proteins/genetics
• Carrier Proteins/metabolism
• Cell Nucleus/genetics
• Cell Nucleus/metabolism
• Cytoplasm/genetics
• Cytoplasm/metabolism
• Dysbindin
• Dystrophin-Associated Proteins
• Fatty Acids, Unsaturated/pharmacology
• Gene Expression Regulation
• HEK293 Cells
• Humans
• Karyopherins/antagonists & inhibitors
• Karyopherins/genetics
• Karyopherins/metabolism
• Mice
• Mice, Mutant Strains
• Presynaptic Terminals/metabolism
• RNA, Messenger/biosynthesis
• RNA, Messenger/genetics
• Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors
• Receptors, Cytoplasmic and Nuclear/genetics
• Receptors, Cytoplasmic and Nuclear/metabolism
• Schizophrenia/genetics
• Schizophrenia/metabolism
• Synapsins/biosynthesis
• Synapsins/genetics
• Exportin 1 Protein

• synaptic vesicle
• growth cone
• axon elongation
• nerve terminal
• neurotransmitter release
• membrane trafficking
• cytoskeleton

• Animals
• Cytoskeleton/metabolism
• Growth Cones/physiology
• Growth Cones/ultrastructure
• Humans
• Neurogenesis/physiology
• Neurons/cytology
• Neurons/physiology
• Phosphorylation
• Protein Isoforms/chemistry
• Protein Isoforms/genetics
• Protein Isoforms/metabolism
• Synapses/physiology
• Synapses/ultrastructure
• Synapsins/chemistry
• Synapsins/genetics
• Synapsins/metabolism
• Synaptic Transmission/physiology

• GGP09134 Telethon

Synapsins are neuronal phosphoproteins involved in several functions correlated with both neurotransmitter release and synaptogenesis. The comprehension of the basal role of the synapsin family is hampered in vertebrates by the existence of multiple synapsin genes. Therefore, studying homologous genes in basal chordates, devoid of genome duplication, could help to achieve a better understanding of the complex functions of these proteins.

In this study we report the cloning and characterization of the Ciona intestinalis and amphioxus Branchiostoma floridae synapsin transcripts and the definition of their gene structure using available C. intestinalis and B. floridae genomic sequences. We demonstrate the occurrence, in both model organisms, of a single member of the synapsin gene family. Full-length synapsin genes were identified in the recently sequenced genomes of phylogenetically diverse metazoans. Comparative genome analysis reveals extensive conservation of the SYN locus in several metazoans. Moreover, developmental expression studies underline that synapsin is a neuronal-specific marker in basal chordates and is expressed in several cell types of PNS and in many, if not all, CNS neurons.

Our study demonstrates that synapsin genes are metazoan genes present in a single copy per genome, except for vertebrates. Moreover, we hypothesize that, during the evolution of synapsin proteins, new domains are added at different stages probably to cope up with the increased complexity in the nervous system organization. Finally, we demonstrate that protochordate synapsin is restricted to the post-mitotic phase of CNS development and thereby is a good marker of postmitotic neurons.