Author: Francesco Sperotto
Date: 05/06/2011




The synapsins are a family of neuronal phosphoproteins evolutionarily conserved in invertebrate and vertebrate organisms with a molecular weight from 63 to 75 KDa. Their best-characterised function is to modulate neurotransmitter release at the pre-synaptic terminal, by reversibly tethering synaptic vesicles (SVs) to the actin cytoskeleton. However, many recent data have suggested novel functions for synapsins in other aspects of the pre-synaptic physiology, such as SV docking, fusion and recycling.
The synapsin (syn) family is composed of ten homologous proteins: syns Ia–b, IIa–b, and IIIa–f.
Synapsins are composed of a highly homologous N-terminal region that can be divided in three domains: A, B and C, and a more variable C-terminal portion composed of differently spliced domains (domains D–I).


In mammals, the different isoforms are generated by alternative splicing of three distinct genes, termed SYN1, SYN2 and SYN3, which have been mapped in human and mouse on chromosome X (Xp11), chromosome 3 (3p25) and chromosome 22 (22q12.3) respectively.

Your Favorite Gene SigmaSYN1SYN2SYN3



Synapsins or synapsin-like molecules have now been identified in a wide range of vertebrate and invertebrate organisms. The most accredited hypothesis to date postulates that the synapsin family originated from one ancestral gene, which was subjected to duplication when vertebrates diverged from invertebrates.


Domain A is a short N-terminal region, shared by all synapsin isoforms. It contains the phosphorylation site (site 1) for PKA, CaMKI and IV. Site 1 is the major phosphorylation site conserved between vertebrate and invertebrate synapsins.

Domain B, rich in small amino acids, displays only a weak similarity between different synapsins, and is considered as a
linker region connecting domain A to domain C. In syn I, domain B contains phosphorylation sites 4 and 5 for mitogen-activated protein kinase (MAPK)/Extracellular signal-regulated kinase (Erk).

Domain C is a large region of about 300 aa, containing both hydrophobic and highly charged sequences with the potential to assume a-helix and b-sheet conformation. It shows extensive homology amongst the various members of the family, and mediates the core functions of synapsins: the interaction with actin filaments and SV phospholipids and synapsin homo- and heterodimerisation. Domain C was found to modulate syn I binding to both SVs and actin through phosphorylation by the Tyr kinase c-Src.

After domain C, the amino acid sequence starts to diverge in the different synapsin gene products. However, all isoforms bear a proline-rich domain namely from D to I.
Domain D is a long, collagenase-sensitive region that contains phosphorylation site 2 for CaMKII, site 3 for CaMKII and p21-activated kinase (PAK), as well as sites 6 and 7 for MAPK/Erk, Cdk1 and Cdk5. Domain D binds to several SH3-containing proteins, such as c-Src, Grb2, the p85 subunit of PI3K, PLC-g and amphiphysin-I and II, as well as to other interactors such as CaMKII and Rab3.



To exert their functions in the pre-synaptic compartment, synapsins need to be anterogradely transported from the cell body to the axon terminals. Multiple pools of newly synthesised synapsin were identified: one pool moving at the rate of fast axonal transport, consistent with the transport of synapsin on pre-assembled SVs, and at least another slower pool possibly associated with cytoskeletal components. More recently, synapsin has been shown to be part of mobile packets that are anterogradely transported along the axon, and contain several pre-synaptic components.

Mass spectrometry analysis on hippocampal tissue has revealed at least 15 distinct synapsin forms, which contain, besides phosphorylation, also N-acetylation, methylation, pyroglutamate, tryptophan oxidation and deamidation sites.
All of these post-translational modifications can alter the interactions properties of synapsin.
Finally synapsins might be degraded in the pre-synaptic terminals via calpain.



Synapsin localised to pre-synaptic terminals to SVs far away from the plasmamembrane (distal pool), as well as to docked vesicles (proximal pool), albeit to a lesser extent. Within the nerve terminals, synapsin was found to be associated with the cytoplasmic surface of small SVs, containing non-peptidergic “classical” neurotransmitters, and virtually absent from large dense-core synaptic vesicles (LDCV) containing neuropeptides.


Synapsins were initially identified as major brain-specific phosphoproteins. They are now known to be substrates for several protein kinases, which all contribute to the modulation of synapsin function.

Sinapsin bind phospholipid membranes and SVs protein, both necessary for efficient vesicles fusion and neurotransmitter release and have been reported to bind virtually all the cytoskeletal components present in the pre-terminal and terminal compartments of the axon: F- and G-actin, spectrin, microtubules and neurofilaments.


Synapsin are also implicated in neurites outgrowth and synapse formation with different role for each isoform as shown below.

The influence of each synapsin isoform on the different biological processes is ranked as mild (0), intermediate (00), or strong (000).

In synaptic transmission synapsin phosphorylation allows an higher release of neurotransmitter, which is involved in several type of synaptic potentiation both in short-term plasticity and long-term plasticity.
Fine regulation of synapsin phosphorylation is a synaptic modification mechanism underlying learning and memory processes.


5′ region of synapsin gene is rich in GC, and contain a consensus motif for the cAMP responsive element (CRE), but no TATA or CAAT consensus elements. In addition, two motifs were identified, which were very similar to sequences found in the regulatory regions of the TrkA and 68 kDa neurofilament protein genes, opening the possibility that a subset of neuronal genes might be under the control of the same factors. Interestingly, although the CRE-binding (CREB) transcription factor was able to bind the CRE sequence in the promoter region of the SYN gene, synapsin transcription did not increase upon forskolin treatment; on the contrary, rising cAMP levels led to a slight decrease of synapsin mRNA. However, the CRE element was shown to bind several nuclear proteins, and to contribute to the basal activation of the syn I gene.
Moreover mutations in the silencer element of the synapsin gene were shown to promote expression in non-neuronal cells, by disrupting the binding of specific transcriptional repressor proteins. One of these factors was later identified in the neuron-restrictive silencer factor (NRSF), also known as repressor element-1 silencing transcription factor (REST), which regulates the transcription of several neuronal genes, including the BDNF gene.


To date there is no diagnostic use of synapsin, however genetic analyses in human populations have identified a nonsense mutation (Identification of a mutation in synapsin I, a synaptic vesicle protein, in a family with epilepsy 2004) in the gene coding for syn I, likely to cause mRNA degradation, as the cause of epilepsy in a family with history of epilepsy alone, or associated with aggressive behaviour, learning disabilities or autism. Several study show that anaesthetic agents decreased the levels of syn I phosphorylation whereas convulsant agents and intermittent amphetamine treatment increased it. Moreover lack of synapsin proteins can generate epileptic seizures involving distinct neuronal populations in different brain areas and is associated with behavioural and learning deficits.
Furthermore disfunction of synapsin proteins is also associated with schizophrenia (2) and other psychoses.

2012-06-07T10:39:25 - Andrea Cerase


At synapses, one of the most common consequences of increasing the spike frequency is a decrease in the quantity of neurotransmitter released at each stimulus, referred to as synaptic depression.
At Aplysia synapses, low frequency induced depression (LFD) can be elicited using sustained stimulations at low frequency (1 Hz). LFD is related neither to a depletion of the ready-to-fuse synaptic vesicles (SVs) nor a decrease in the release probability, but results from the silencing of a subpopulation of release sites. A subset of SVs or release sites, which acquired a higher release probability status during LFD, permits synapses to rapidly and temporarily recover the initial synaptic strength when the stimulation is stopped. However, the recovery of the full synaptic capacity to sustain repetitive stimulations is slow and involves spontaneous reactivation of the silent release sites. Application of tetanic stimulations accelerates this recovery by immediately switching on the silent sites. This high-frequency-dependent phenomenon underlies a new form of synaptic plasticity that allows resetting of presynaptic efficiency independently from the recent history of the synapse. Synapsin has a role in this process affecting the kinetics of LFD and recovery from depression. Either microinjection of a mutated Aplysia synapsin that can not be phosphorylated by cAMP-dependent protein kinase (PKA), or the PKA inhibitor (peptide 6–22 amide; PKAi6–22) both prevented high-frequency-dependent awakening of release sites.
Unsilencing has a very slow time constant (>40 min) in absence of any neuronal activity but it rapidly became faster when neurons are stimulated. This recovery is speeded up when synapsin is neutralized by anti-Syn antibodies but no such effect is detected after injection of ApSyn mutated in PKA-site 1 (Ser9-Ala mutation) or PKA-inhibitor. This clearly reveals a role for PKA-phosphorylated synapsin in the release site reactivation. Possibly, application of a burst of high frequency spiking induces elevation of cAMP concentration in the vicinity of release sites and stimulates phosphorylation of synapsin present at the release site thereby bypassing or reversing the molecular events underlying silencing of release sites.


Another form of short-term plasticity is PTP: bursts of action potentials at 20–50 Hz rates often trigger post-tetanic potentiation (PTP), that consist in short-term increase of synaptic efficacy due to higher release probability and increased supply of readily releasable synaptic vesicles.
PTP exhibits a time-course in the order of seconds, a time sufficiently long to involve SV mobilisation from the reserve pool.
The action of synapsins on PTP is consistent with the pre-docking model, in which presynaptic
Ca2+ accumulation induced by tetanic stimulation triggers the Ca2+-dependent phosphorylation of synapsins and the subsequent release of SVs from the actin cytoskeleton and increased availability for exocytosis. Thus, the role of synapsins in PTP would determine an activity dependent transition of SVs from reserve pool to readily releasable pool.
In the last studies, a central role of synapsins in PTP has been assigned in invertebrates. In fact, both mouse and invertebrate synapses exhibit a marked impairment in PTP after genetic deletion or neutralisation of syn I and/or syn II. At Aplysia synapses, inactivation of synapsin by specific antibodies, injection of non-phosphorylated forms of ApSyn or PKA peptidic inhibitory completely abolished PTP, without affecting basal neurotransmission.
Similarly, at Helix synapses, the phosphorylation of site 1 helSyn, provided both by PKA and CaMKI/IV, is necessary for PTP.
Moreover, recent evidence points for a crucial role of the MAPK/Erk phosphorylation at the conserved sites 4 and 5 of synapsin in the expression of PTP at this synapse, suggesting that PTP is associated with the phosphorylation of several synapsin sites by distinct kinases that are concurrently activated by tetanic stimulation. In this system, overexpression of non-phosphorylatable synapsin mutants at the level of the pre-synaptic neuron results in impaired PTP, thus suggesting that upon sustained electrical stimulation MAPK/Erk signalling might regulate SV availability at least in part by phosphorylation of synapsin proteins.
Interestingly, together with vertebrate data obtained using various synapsin mutants, invertebrate data consistently go against the seminal model implicating phosphorylation of sites 2 and 3 by CaMKII during PTP, leading to the mobilization of the reserve SV pool. Indeed, domain D is poorly conserved in invertebrate synapsin bearing sites 2 and 3, a likely explanation for their weak phosphorylation by CaMKII.

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