Synaptic vesicle glycoprotein 2 (SV2)
Synaptic vesicle glycoprotein 2 (SV2) family and SV2-related protein (SVOP) are transporter-like proteins that are located in synaptic neurotransmitter-containing vesicles. These have structural similarities with the major facilitator (MF) family of small molecule transporters, including GLUTs. SV2 and SVOP are involved in the regulated secretion of neurotransmitters from presynaptic neurons (Nowack et al., 2010), possibly via synaptic vesicle recycling. The three SV2 genes in mammals encode three isoforms SV2A, SV2B, and SV2C. SV2A is ubiquitously and homogeneously located in presynaptic vesicle membranes across the brain, while SV2B and SV2C have more restricted distribution (Bajjalieh et al., 1994; Janz & Südhof, 1999; Bartholome et al., 2017). Each vesicle membrane contains ∼5 SV2 molecules, with little variation (Mutch et al., 2011). SVOP is distantly related to SV2 family proteins with 20-22% homology, and is present also in neuronal cell bodies, while SV2 proteins are only found in synapses. SVOP is evolutionarily conserved protein in vertebrates and invertebrates.
Botulinum neurotoxins use certain synaptic proteins, including SV2 isoforms, as receptors for entry into neurons (Baldwin & Barbieri, 2009).
SV2A is present ubiquitously in the adult brain (including trigeminal nuclei and sphenopalatine ganglion) (Bartholome et al., 2017). SV2A expression level correlates well with classical markers of presynaptic terminals, such as synaptophysin and synaptotagmin. Therefore SV2A can be considered as a marker of synaptic density in the brain. SV2A is the binding site of racetam family of epilepsy drugs, including brivaracetam and levetiracetam. SV2A modulates epileptogenesis via GABAergic, but not glutamatergic system (Ohno & Tokudome, 2017).
Levetiracetam has been labelled with 11C (Cai et al., 2014), but several other PET tracers for SV2A have been developed (Warnock et al., 2014; Estrada et al., 2016; Nabulsi et al., 2016; Li et al., 2019; Patel et al., 2020). [11C]UCB-J binds specifically to SV2A, and has favourable kinetics to be used to assess the synaptic density in vivo in humans (Nabulsi et al., 2016; Finnema et al., 2016). [18F]SynVesT-1 ([18F]MNI-1126, (R)-[18F]SDM-8) may have faster kinetics than [11C]UCB-J (Cai et al., 2018; Li et al., 2018, 2019, and 2021; Naganawa et al., 2021). [18F]SynVesT-1 has shown similar brain distribution as [11C]UCB-J, and higher BPND when centrum semiovale (white matter underneath the cerebral cortex) was used as reference region (Constantinescu et al., 2019; Naganawa et al., 2021). Both [11C]UCB-J and [18F]SynVesT-1 have excellent test-retest reproducibility (Li et al., 2021). Scan durations of 30-120 min with [18F]SynVesT-1 provide similar test-retest reproducibility (Li et al., 2021). [18F]UCB-H has been found to be specific for SV2A against SV2B and SV2C in rats (Serrano et al., 2019), and SUV from static 20-40 min scan correlated well with VT (Serrano et al., 2020). The specific binding of [18F]UCB-H is relatively low, hampering quantification (Goutal et al., 2021).
Reductions in SV2A binding have been seen around the epileptic focus in temporal lobe epilepsy patients, in the cortical areas of patients with mood disorders, PTSD, schizophrenia, Alzheimer's disease, and ALS (Rabiner, 2018; Holmes et al., 2019; Onwordi et al., 2020; Tang et al., 2022). Synaptic loss has been seen in brainstem nuclei in Parkinson's disease (Matuskey et al., 2020). [11C]UCB-J has also been used to assess SV2A occupancy of anti-epileptic drugs (Rabiner, 2018; Finnema et al., 2019).
SV2A is expressed not only in the brain, but also in neuroendocrine cells and at neuromuscular junctions (Bartholome et al., 2017). SV2A could serve as a target for PET imaging in neuroendocrine prostate cancer (Guan et al., 2021).
SV2B expression is high in the cortex and hippocampus, but it is absent in the globus pallidus, hippocampal dentate gyrus, reticular substantia nigra, and reticular thalamic nucleus (Bartholome et al., 2017; Hu et al., 2017). Expression of SV2B seems to be restricted to some glutamatergic neurons.
In humans, SV2C is expressed in evolutionarily old brain regions, including striatum, substantia nigra nuclei in the pons and medulla oblongata. Low levels are found in olfactory bulb, cerebrum, cerebellum, and hippocampus (Bartholome et al., 2017). SV2C is expressed in dopaminergic neurons, certain GABAergic neurons, such as Purkinje cells of the cerebellum, and in some cholinergic neurons (Bartholome et al., 2017). SV2C regulates dopamine release (Dunn et al., 2017), and is involved in hypertension, venous thromboembolism and coagulation pathways (Janz & Südhof, 1999; Hu et al., 2017).
Acebes A. Brain mapping and synapse quantification in vivo: it's time to imaging. Front Neuroanat. 2017; 11:17. doi: 10.3389/fnana.2017.00017.
Bartholome O, Van den Ackerveken P, Sánchez Gil J, de la Brassinne Bonardeaux O, Leprince P, Franzen R, Rogister B. Puzzling out synaptic vesicle 2 family members functions. Front Mol Neurosci. 2017; 10: 148. doi: 10.3389/fnmol.2017.00148.
Dunn AR, Stout KA, Ozawa M, Lohr KM, Hoffman CA, Bernstein AI, Li Y, Wang M, Sgobio C, Sastry N, Cai H, Caudle WM, Miller GW. Synaptic vesicle glycoprotein 2C (SV2C) modulates dopamine release and is disrupted in Parkinson disease. Proc Natl Acad Sci U S A 2017; 114(11): E2253-E2262. doi: 10.1073/pnas.1616892114.
Finnema SJ, Nabulsi NB, Eid T, Detyniecki K, Lin S, Chen M-K, Dhaher R, Matuskey D, Baum E, Holden D, Spencer DD, Mercier J, Hannestad J, Huang Y, Carson RE. Imaging synaptic density in the living human brain. Sci Transl Med. 2016; 8: 348ra96. doi: 10.1126/scitranslmed.aaf6667.
Heurling K, Ashton NJ, Leuzy A, Zimmer ER, Blennow K, Zetterberg H, Eriksson J, Lubberink M, Schöll M. Synaptic vesicle protein 2A as a potential biomarker in synaptopathies. Mol Cell Neurosci. 2019; 97:34-42. doi: 10.1016/j.mcn.2019.02.001.
Hu YW, Xiao L, Zheng L, Wang Q. Synaptic vesicle 2C and its synaptic-related function. Clin Chim Acta 2017; 472: 112-117. doi: 10.1016/j.cca.2017.07.029.
Löscher W, Gillard M, Sands ZA, Kaminski RM, Klitgaard H. Synaptic vesicle glycoprotein 2A ligands in the treatment of epilepsy and beyond. CNS Drugs 2016; 30(11): 1055-1077. doi: 10.1007/s40263-016-0384-x.
Mercier J, Provins L, Valade A. Discovery and development of SV2A PET tracers: Potential for imaging synaptic density and clinical applications. Drug Discov Today Technol. 2017; 25:45-52. doi: 10.1016/j.ddtec.2017.11.003.
Nabulsi NB, Mercier J, Holden D, Carré S, Najafzadeh S, Vandergeten MC, Lin SF, Deo A, Price N, Wood M, Lara-Jaime T, Montel F, Laruelle M, Carson RE, Hannestad J, Huang Y. Synthesis and preclinical evaluation of 11C-UCB-J as a PET tracer for imaging the synaptic vesicle glycoprotein 2A in the brain. J Nucl Med. 2016; 57(5): 777-784. doi: 10.2967/jnumed.115.168179.
Nowack A, Yao J, Custer KL, Bajjalieh SM. SV2 regulates neurotransmitter release via multiple mechanisms. Am J Physiol Cell Physiol. 2010; 299(5): C960-C967. doi: 10.1152/ajpcell.00259.2010.
Rabiner EA. Imaging synaptic density: a different look at neurological diseases. J Nucl Med. 2018; 59(3): 380-381. doi: 10.2967/jnumed.117.198317.
Vogl C, Tanifuji S, Danis B, Daniels V, Foerch P, Wolff C, Whalley BJ, Mochida S, Stephens GJ. Synaptic vesicle glycoprotein 2A modulates vesicular release and calcium channel function at peripheral sympathetic synapses. Eur J Neurosci. 2015; 41(4): 398-409. doi: 10.1111/ejn.12799.
Yao J, Bajjalieh SM. SVOP is a nucleotide binding protein. PLoS One 2009; 4(4): e5315. doi: 10.1371/journal.pone.0005315.
Updated at: 2022-11-29
Created at: 2017-11-28
Written by: Vesa Oikonen