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Study of the SV2A protein role in Epilepsy

Odile Bartholomé1*, Priscilla Van Den Ackerveken1, Catherine Menten Dedoyard1, Maria Elisa Serrano Navacerrada2, Judit Sanchez Gil1, Virginie Neirinckx1, Guillaume Becker2, Alain Plenevaux2, Sabine Wislet1 and Bernard Rogister1
  • 1 Université de Liège, GIGA-Neurosciences, Belgium
  • 2 Université de Liège, Centre de Recherche du Cyclotron, Belgium

The SV2A protein is a glycoprotein present in the membranes of most synaptic vesicles. The SV2 protein family includes SV2A but also two other isoforms, SV2B and SV2C [1,2]. Although it is highly conserved during evolution, its physiological role remains largely unknown. However, it has recently been demonstrated that levetiracetam (Keppra®) a very effective drug in epilepsy binds to this SV2A protein [3]. Moreover, in epileptic foci resected in humans with intractable temporal lobe epilepsy, SV2A expression is down-regulated while SV2C is up-regulated [4]. Currently we do not know much about the normal function of SV2A and its possible involvement in diseases such as epilepsy. This project aims to better understand how the SV2A protein may be involved in the occurrence of epilepsy. For this purpose, we engineered a mouse line that allows the conditional removal of SV2A in hippocampal region (CA3 and dentate gyrus (DG)) from the postnatal stages 15 (P15) (Sv2A-cKO). We observed a significant reduction of SV2A proteins and transcripts concentrations in hippocampus of Sv2A-cKO animals in comparison with the wild-type (WT). Together, these results confirmed the efficiency of the invalidation of SV2A in our mouse model. In parallel, we did not measure any significant change in SV2B or SV2C expression, two other member of SV2 family, implying the absence of compensation phenomenon. Finally, our preliminary results show that SV2A-cKO adult animals did not exhibit spontaneous seizure or a decreased threshold of seizures in a PTZ model. Ongoing experiments are designed to identify more precisely Sv2A-cKO phenotype. Résumé en Franças: Les mécanismes cellulaires qui sont la cause de l’épilepsie sont encore très mal connus. Notre groupe a récemment mis en évidence (cf référence 4) des modifications de la concentration d’une protéine nommée SV2 (qui existe sous 2 isoformes SV2a et SV2b) chez des patients épileptiques. SV2 est localisée au niveau des terminaisons neuronales mais de fonctions inconnues. Afin d’élucider le (ou les) rôle(s) de cette protéine nous avons mis au point un modèle de souris qui nous permet de modifier la concentration de SV2 et ainsi d’étudier au niveau cellulaire, l’effet de cette modification. Samenvatting in het Nederlands: Mechanismen op celniveau die epilepsie veroorzaken, zijn nog erg slecht gekend. Onze werkgroep heeft onlangs aangetoond dat bij patiënten met epilepsie de concentratie van een eiwit genaamd SV2 (voorkomend als twee iso-vormen SV2a en SV2b) veranderd is. SV2 bevindt zich op de zenuwuiteinden, maar de functie ervan is nog ongekend. Om de rol van dit eiwit op te helderen, hebben we een muismodel ontwikkeld dat toelaat de concentratie SV2 te wijzigen en dus de uitwerking van deze wijziging op celniveau te onderzoeken.

References

[1] Bajjalieh, S. M., Frantz, G. D., Weimann, J. M., McConnell, S. K., & Scheller, R. H. (1994). Differential expression of synaptic vesicle protein 2 (SV2) isoforms. The Journal of Neuroscience, 14(9), 5223–35.
[2] Janz, R., & Südhof, T. C. (1999). SV2C is a synaptic vesicle protein with an unusually restricted localization: Anatomy of a synaptic vesicle protein family. Neuroscience, 94(4), 1279–1290.
[3] Lynch, B. A., Lambeng, N., Nocka, K., Kensel-Hammes, P., Bajjalieh, S. M., Matagne, A., & Fuks, B. (2004). The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci U S A, 101(26), 9861–9866.
[4] Crèvecœur, J., Kaminski, R. M., Rogister, B., Foerch, P., Vandenplas, C., Neveux, M., Mazzuferi, M., Kroonen, J., Poulet, C., Martin, D., Sadzot, B., Rikir, E., Klitgaard, H., Moonen, G., Deprez, M. (2014). Expression pattern of synaptic vesicle protein 2 (SV2) isoforms in patients with temporal lobe epilepsy and hippocampal sclerosis. Neuropathology and Applied Neurobiology, 40(2), 191-204.

Keywords: Epilepsy, Temporal Lobe, Hippocampus, SV2A., Synaptic Vesicles, mouse models

Conference: 6th Belgian Brain Congress, MONS, Belgium, 8 Oct - 8 Oct, 2016.

Presentation Type: Poster Presentation

Topic: Brain and brain diseases: between heredity and environment

Citation: Bartholomé O, Van Den Ackerveken P, Menten Dedoyard C, Serrano Navacerrada M, Sanchez Gil J, Neirinckx V, Becker G, Plenevaux A, Wislet S and Rogister B (2016). Study of the SV2A protein role in Epilepsy. Conference Abstract: 6th Belgian Brain Congress. doi: 10.3389/conf.fnagi.2016.03.00007

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Received: 23 Jun 2016; Published Online: 24 Jun 2016.

* Correspondence: MD, PhD. Odile Bartholomé, Université de Liège, GIGA-Neurosciences, Liège, 4000, Belgium, odile.bartholome@ulg.ac.be