Expression of SV2 isoforms during rodent brain development

Crevecoeur, Julie; Foerch, Patrik; Doupagne, Melissa; Thielen, Caroline; Vandenplas, Catherine; Moonen, Gustave; Deprez, Manuel; Rogister, Bernard

doi:10.1186/1471-2202-14-87

Cited by 43 publications

(41 citation statements)

References 46 publications

(54 reference statements)

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“…Mice lacking SV2A generated by targeted gene disruption [34] appear normal at birth, but do not grow normally; they express seizures and die within 3 weeks, suggesting multiple neural alterations. Interestingly, hippocampal SV2A expression increases in wild-type mice between postnatal day (PND) 5 and 7, and remains stable from PND 7–10 [35]. The observed alterations of SV2A expression in hippocampus are consistent with the appearance of seizures in SV2A knockout animals at early postnatal age and the hypothesis that SV2A absence favors epileptic seizures.…”

Section: The Role Of Sv2a In Modulating Neuronal Excitability In the mentioning

confidence: 79%

Synaptic Vesicle Glycoprotein 2A Ligands in the Treatment of Epilepsy and Beyond

Löscher¹,

et al. 2016

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The synaptic vesicle glycoprotein SV2A belongs to the major facilitator superfamily (MFS) of transporters and is an integral constituent of synaptic vesicle membranes. SV2A has been demonstrated to be involved in vesicle trafficking and exocytosis, processes crucial for neurotransmission. The anti-seizure drug levetiracetam was the first ligand to target SV2A and displays a broad spectrum of anti-seizure activity in various preclinical models. Several lines of preclinical and clinical evidence, including genetics and protein expression changes, support an important role of SV2A in epilepsy pathophysiology. While the functional consequences of SV2A ligand binding are not fully elucidated, studies suggest that subsequent SV2A conformational changes may contribute to seizure protection. Conversely, the recently discovered negative SV2A modulators, such as UCB0255, counteract the anti-seizure effect of levetiracetam and display procognitive properties in preclinical models. More broadly, dysfunction of SV2A may also be involved in Alzheimer’s disease and other types of cognitive impairment, suggesting potential novel therapies for levetiracetam and its congeners. Furthermore, emerging data indicate that there may be important roles for two other SV2 isoforms (SV2B and SV2C) in the pathogenesis of epilepsy, as well as other neurodegenerative diseases. Utilization of recently developed SV2A positron emission tomography ligands will strengthen and reinforce the pharmacological evidence that SV2A is a druggable target, and will provide a better understanding of its role in epilepsy and other neurological diseases, aiding in further defining the full therapeutic potential of SV2A modulation.

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Section: The Role Of Sv2a In Modulating Neuronal Excitability In the mentioning

confidence: 79%

Synaptic Vesicle Glycoprotein 2A Ligands in the Treatment of Epilepsy and Beyond

Löscher¹,

et al. 2016

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“…We thus concluded that the adult Grik4:SV2A-cKO mice were neither subject to spontaneous epileptic seizures nor characterized by lower epileptic thresholds, despite presenting reduced levels of hippocampal SV2A protein. Interestingly, in human epileptic foci, the down-regulation of SV2A expression is associated with an overexpression of SV2C [18]. We thus investigated if the levels of other proteins of the SV2 family were affected while SV2A is strongly reduced.…”

Section: Resultsmentioning

confidence: 99%

“…An investigation of the half-live of SV2A could help us to clarify this situation. Secondly, SV2A proteins are detected as early as the first 12 days of embryogenesis (E12), including in the hippocampus [18]. It is thus possible that any impact of SV2A on epileptogenesis observed at approximately P7 in an SV2A-KO mouse is more likely a consequence of SV2A, rather than a role restricted to the developmental stages of the hippocampus.…”

Section: Discussionmentioning

confidence: 99%

Development and Validation of a New Mouse Model to Investigate the Role of SV2A in Epilepsy

et al. 2016

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SV2A is a glycoprotein present in the membranes of most synaptic vesicles. Although it has been highly conserved throughout evolution, its physiological role remains largely unknown. Nevertheless, Levetiracetam, a very effective anti-epileptic drug, has been recently demonstrated to bind to SV2A. At present, our understanding of the normal function of SV2A and its possible involvement in diseases like epilepsy is limited. With this study, we sought to develop a relevant model enabling analysis of SV2A’s role in the occurrence or progression of epilepsy. For this purpose, we generated a floxed SV2A mouse model with conditional alleles carrying LoxP sites around exon 3 by means of a gene-targeting strategy. The SV2A lox/lox mouse line is indistinguishable from wild-type mice. When the recombination was observed in all cells, a model of mice with both SV2A alleles floxed around exon 3 recapitulated the phenotype of SV2A KO mice, including seizures. However, the specific invalidation of SV2A in the CA3 hippocampal region was not followed by epileptic seizures or decrease in the epileptic threshold on pentylenetetrazol (PTZ) test. These results demonstrate that the floxed SV2A mouse line has been successfully established. This transgenic mouse model will be useful for investigating SV2A functions related to cell types and developmental stages.

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“…5). In particular, VPA increased the expression of the neuronal marker βIII-tub, in parallel with a higher expression of synaptic vesicle protein 2 (SV2), an integral membrane protein expressed in synaptic vesicles [42,43], suggesting commitment of OPCs towards neuroblasts that are acquiring proteins typically involved in synaptic transmission.…”

Section: Valproic Acid Fosters the Neuronal Commitment Of Opcs And Momentioning

confidence: 99%

A new role for the P2Y-like GPR17 receptor in the modulation of multipotency of oligodendrocyte precursor cells in vitro

Boccazzi

Lecca

Marangon

et al. 2016

Purinergic Signalling

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Oligodendrocyte precursor cells (OPCs, also called NG2 cells) are scattered throughout brain parenchyma, where they function as a reservoir to replace lost or damaged oligodendrocytes, the myelin-forming cells. The hypothesis that, under some circumstances, OPCs can actually behave as multipotent cells, thus generating astrocytes and neurons as well, has arisen from some in vitro and in vivo evidence, but the molecular pathways controlling this alternative fate of OPCs are not fully understood. Their identification would open new opportunities for neuronal replace strategies, by fostering the intrinsic ability of the brain to regenerate. Here, we show that the anti-epileptic epigenetic modulator valproic acid (VPA) can promote the generation of new neurons from NG2 + OPCs under neurogenic protocols in vitro, through their initial de-differentiation to a stem cell-like phenotype that then evolves to Bhybrid^cell population, showing OPC morphology but expressing the neuronal marker βIII-tubulin and the GPR17 receptor, a key determinant in driving OPC transition towards myelinating oligodendrocytes. Under these conditions, the pharmacological blockade of the P2Y-like receptor GPR17 by cangrelor, a drug recently approved for human use, partially mimics the effects mediated by VPA thus accelerating cells' neurogenic conversion. These data show a co-localization between neuronal markers and GPR17 in vitro, and suggest that, besides its involvement in oligodendrogenesis, GPR17 can drive the fate of neural precursor cells by instructing precursors towards the neuronal lineage. Being a membrane receptor, GPR17 represents an ideal Bdruggable^target to be exploited for innovative regenerative approaches to acute and chronic brain diseases.

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Expression of SV2 isoforms during rodent brain development

Cited by 43 publications

References 46 publications

Synaptic Vesicle Glycoprotein 2A Ligands in the Treatment of Epilepsy and Beyond

Synaptic Vesicle Glycoprotein 2A Ligands in the Treatment of Epilepsy and Beyond

Development and Validation of a New Mouse Model to Investigate the Role of SV2A in Epilepsy

A new role for the P2Y-like GPR17 receptor in the modulation of multipotency of oligodendrocyte precursor cells in vitro

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