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Behavioural phenotyping of SV2A lox/lox mice: Motor and anxiety-like features

Maria Elisa Serrano Navacerrada1, 2*, Odile Bartholome3, Priscilla Van Den Ackerveken3, 4, Bernard Rogister3, Alain Plenevaux1 and Ezio Tirelli2
  • 1 Université de Liège, GIGA-CRC In vivo imaging, Belgium
  • 2 Université de Liège, Neuroscience comportementale et psychopharmacologie expérimentale, Belgium
  • 3 Université de Liège, Biochimie et physiologie générales, et biochimie humaine, Belgium
  • 4 Université de Liège, Département des sciences biomédicales et précliniques, Belgium

Background: Epilepsy is one of the most common neurological disorders (1). Current anti-epileptic drugs, such as Levetiracetam (Keppra®) or Brivaracetam, mainly target the trans-membrane Synaptic Vesicle Protein 2A (2). Homozygous SV2A KO mice have been shown to suffer severe seizures and die within 3 weeks (3), establishing a link between this protein and the epilepsy. In 2009, the availability of heterozygous SV2A (+/-) mice as research tool enabled shedding some light on the role of protein SV2A, revealing no motor differences but anxiety-like features in these mice compared with the WT (4), and a pro-epileptic phenotype (3,5,6). Recently, a floxed SV2A mouse model has been produced with the Cre/loxP recombination system. This model allows invalidating the protein in CA3 hippocampal region, but without being associated to epileptic seizures (7). Objectives: Perform a first behavioural phenotyping of SV2A lox/lox mice. Methodology: Two experiments were conducted in parallel to evaluate the effect of 3 different genotypes in the phenotype: WT (Grik4-/-, SV2A lox/lox), HZ (Grik4 +/-, SV2A lox/+) and cKO (Grik4 +/-, SV2A lox/lox) in male (n = 42) and female (n = 33) separately. Mice were housed individually throughout the experiment, with standard food and water ad libitum. After an acclimatization period of 2 weeks, anxiety-like features as well as exploration abilities were evaluated in an elevated plus-maze (EPM; single session of 5 minutes). Three days later, spontaneous locomotor activity and habituation to the environment were measured over three one-hour once-daily successive sessions using activity chambers (ACT). Results: One-way ANOVA in EPM data presented no significant differences between genotypes, either in males or in females. Note that a significant difference was found, between time spent in close arms vs open arms (males: η2p = 0.738; F = 150.248; females: η2p = 0.805; F = 271.504, both at p<0.01). Mixed model ANOVA on the ACT data revealed no significant differences between genotypes in either sexes, the levels of spontaneous locomotor activity and habituation being comparable across genotypes (p>0.05). Habituation occurred normally as supported by the main effect of successive sessions (males: η2p = 0.716; F = 46.562; females: η2p = 0.663; F = 28.558, both at p<0.01). Conclusion: Results indicate that a decrease in the hippocampal expression of SV2A protein does not lead to major behavioral changes at least in the model tested. Regarding locomotor activity, the results found in heterozygous SV2A (+/-) mice are in line with those of Lamberty et al., 2009 (4). However, our mice did not present anxiety-like features. Highly-anxious heterozygous SV2A (+/-) mice exhibit a 50%- lack of SV2A in the whole brain. Thus the confinement of the SV2A reduction to the hippocampus is perhaps insufficient for such an effect to be expressed. Since the power of the present design is lower than 60%, tests with a power of 80% are being conducted (larger sample size), such that any existing small effect size will be detected. An additional test to evaluate the spatial memory may help us better understand the effect that a specific reduction in SV2A hippocampal expression has on the phenotype of mice.

Acknowledgements

This work was funded by University of Liège, F.R.S.-FNRS, Walloon Region and UCB Pharma. Alain Plenevaux is research director from F.R.S.-FNRS.

References

1. Pati, S. and Alexopoulos, A. V. (2010). Pharmacoresistant epilepsy: from pathogenesis to current and emerging therapies. Cleve Clin J Med, 77(7), 457-567.
2. Hamann, M., Sander, S.E. and Richter, A. (2008). Brivaracetam and seletracetam, two new SV2A ligands, improve paroxysmal dystonia in the dt sz mutant hamster. European journal of pharmacology, 601(1), pp.99-102.
3. Crowder, K.M., Gunther, J.M., Jones, T.A., Hale, B.D., Zhang, H.Z., Peterson, M.R., Scheller, R.H., Chavkin, C. and Bajjalieh, S.M., (1999). Abnormal neurotransmission in mice lacking synaptic vesicle protein 2A (SV2A). Proceedings of the National Academy of Sciences, 96(26), pp.15268-15273.
4. Lamberty, Y., Detrait, E., Leclercq, K., Michel, A. and De Ryck, M., (2009). Behavioural phenotyping reveals anxiety-like features of SV2A deficient mice. Behavioural brain research, 198(2), pp.329-333.
5. Kaminski, R.M., Matagne, A., Leclercq, K., Gillard, M., Michel, P., Kenda, B., Talaga, P. and Klitgaard, H. (2008). SV2A protein is a broad-spectrum anticonvulsant target: functional correlation between protein binding and seizure protection in models of both partial and generalized epilepsy. Neuropharmacology, 54(4), pp.715-720.
6. Kaminski, R.M., Gillard, M., Leclercq, K., Hanon, E., Lorent, G., Dassesse, D., Matagne, A. and Klitgaard, H. (2009). Proepileptic phenotype of SV2A‐deficient mice is associated with reduced anticonvulsant efficacy of levetiracetam. Epilepsia, 50(7), pp.1729-1740.
7. Menten-Dedoyart, C., Navacerrada, M.E.S., Bartholome, O., Gil, J.S., Neirinckx, V., Wislet, S., Becker, G., Plenevaux, A., Van den Ackerveken, P. and Rogister, B. (2016). Development and Validation of a New Mouse Model to Investigate the Role of SV2A in Epilepsy. PloS one, 11(11), p.e0166525.

Keywords: Epilepsy, SV2A protein, Cre/loxP mouse, Elevated plus maze (EPM), locomotor activity, behavioural neuroscience

Conference: 12th National Congress of the Belgian Society for Neuroscience, Gent, Belgium, 22 May - 22 May, 2017.

Presentation Type: Oral Presentation

Topic: Cognition and Behavior

Citation: Serrano Navacerrada M, Bartholome O, Van Den Ackerveken P, Rogister B, Plenevaux A and Tirelli E (2019). Behavioural phenotyping of SV2A lox/lox mice: Motor and anxiety-like features. Front. Neurosci. Conference Abstract: 12th National Congress of the Belgian Society for Neuroscience. doi: 10.3389/conf.fnins.2017.94.00056

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Received: 24 Apr 2017; Published Online: 25 Jan 2019.

* Correspondence: Mrs. Maria Elisa Serrano Navacerrada, Université de Liège, GIGA-CRC In vivo imaging, Liège, 4000, Belgium, meserrano@ulg.ac.be