Behavioral alterations occurring in the 6 Hz corneal kindling model of limbic epilepsy.
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1
Vrije Universiteit Brussel, Department of Pharmaceutical Chemistry and Drug Analysis, Belgium
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2
Vrije Universiteit Brussel, Department of Pharmaceutical Biotechnology and Molecular Biology, Belgium
Epilepsy is a neurological disorder which yearly affects 2.4 million people of all ages and social backgrounds (1). Despite many steps that have been taken towards the development of more effective therapies, antiepileptic drugs still fail to control seizures in approximately 30% of patients with epilepsy (2). Together with chronic unpredictable seizures, a variety of comorbidities, such as memory and cognitive dysfunctions and psychiatric symptoms, affects 1 in 2 patients with epilepsy, further deteriorating their quality of life (3). Unarguably, the validation of robust animal models which mimic drug refractoriness and comorbidities is a hot topic in therapeutic epilepsy research.
Resistance to antiepileptic drugs was recently observed in the 6 Hz corneal kindling model (4) and this non-invasive, inexpensive and reliable model could thus provide a valid alternative to well-established models of epilepsy. However, due to its novelty, an in-depth characterization of the molecular alterations and behavioral changes occurring in the 6 Hz corneal kindling model has not yet been provided. Therefore, after inducing the “fully kindled state” (defined as 10 consecutive generalized seizures) in male NMRI mice via sub-convulsive corneal stimulations, we performed an elaborate battery of behavioral tests in order to evaluate spontaneous locomotor activity, possible cognitive impairments, and psychiatric-like symptoms. Afterwards, we evaluated neuronal activation comparing c-Fos positive cells in the dentate gyrus of mock-stimulated and kindled mice.
We show that 6 Hz corneal kindling does not induce anxiety-like behavior in NMRI mice, as no significant differences between mock-stimulated and kindled mice are observed neither in the time spent in the center of the open field arena nor in the open arms of the elevated plus maze. However a consistent hyper-locomotion in the kindled mice is demonstrated by significantly increased distance travelled in the open field test and number of entries in the Y maze spontaneous alternations test. This hyperactive feature induces a strong bias in the mouse tail suspension and novelty suppressed feeding tests, making it difficult to evaluate depression-like behavior. Furthermore 6 Hz corneal kindling strongly impairs short-term memory, as it induces a decreased preference and time spent in the novel arm in the delayed Y-maze test. No differences are observed in the Y-maze spontaneous alternations test used to evaluate working memory. Our kindling paradigm also induces strong neuronal activation in the dentate gyrus, a region often recruited in pharmacoresistant forms of epilepsy.
To the best of our knowledge, our behavioral characterization depicts for the first time psychotic-like symptoms occurring in the 6 Hz corneal kindling model. Although it requires more research to elucidate whether or not those symptoms can be reversed using anti-psychotic drugs, these data suggest that the 6 Hz corneal kindling model may be used not only to investigate mechanisms of epileptogenesis but also to mimic some comorbidities of epilepsy.
Samenvatting in het Nederlands:
Eén op twee epilepsiepatiënten vertoont ook een geheugen-, verstandelijke of psychiatrische stoornis. Er bestaat een goedkoop, niet-invasief en betrouwbaar muismodel van limbische epilepsie, dat tot stand gebracht wordt door elektrische prikkeling (6Hz) van het hoornvlies. Nochtans ontbreekt een diepgaande kennis over de moleculaire en gedragsveranderingen ervan. We onderwierpen daarom aldus epileptisch geprikkelde muizen én schijn-geprikkelde muizen aan een batterij van gedragstests. We konden aantonen dat het muismodel geen angststoornis, maar wel een overmatig loopgedrag en een stoornis van het kortetermijngeheugen vertoont, bovendien een versterkte zenuwactiviteit in de gyrus dentatus, een hersengebied vaak betrokken bij farmacoresistente epilepsie. Verder onderzoek is vereist om te achterhalen of deze symptomen omkeerbaar zijn door antipsychotische middelen.
Résumé en Français
Un patient épileptique sur deux souffre également de troubles psychotiques. Afin de pouvoir étudier le mécanisme de ces troubles additionnels, nous avons utilisé un modèle animal rendu épileptique par une série de stimulations électriques de 6 Hz de la cornée. Notre étude a porté sur la réalisation de tests comportementaux qui détectent ces troubles additionnels.
Nos résultats ont montré que ces souris épileptiques présentaient deux comportements psychotiques additionnels : une augmentation de l’activité locomotrice et des troubles de la mémoire à court termes. Des analyses morphologiques ont également montré que des neurones du gyrus dentelé, une région du cerveau connue pour être impliquée chez les patients présentant une épilepsie pharmaco-résistante, étaient activés. Ce modèle animal épileptique et psychotique devrait permettre d’analyser les aspects bénéfiques de drogues connue comme anti-psychotiques à la fois sur l’épilepsie et le comportement psychotique.
Acknowledgements
The authors acknowledge the Fund for Scientific Research Flanders, the Queen Elisabeth Medical Foundation, and the Vrije Universiteit Brussel for financial support.
References
1. World Health Organization “Epilepsy: Fact Sheet.” WHO, May 2015. Web. 5 Oct 2015.
2. Laxer et al. “The consequences of refractory epilepsy and its treatment.” Epilepsy Behav. 2014 Aug; 37:59-70. doi: 10.1016/j.yebeh.2014.05.031.
3. Wilner et al. “Common comorbidities in women and men with epilepsy and the relationship between number of comorbidities and health plan paid costs in 2010.” Epilepsy Behav. 2014 Mar; 32:15-20. doi: 10.1016/j.yebeh.2013.12.032.
4. Leclercq et al. “Low potency and limited efficacy of antiepileptic drugs in the mouse 6 Hz corneal kindling model.” Epilepsy Res. 2014 May; 108(4):675-83. doi: 10.1016/j.eplepsyres.2014.02.013.
Keywords:
Epilepsy,
kindling model,
psychiatric symptoms,
Pharmacoresistant epilepsy,
Behavior
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:
Albertini
G,
Walrave
L,
Demuyser
T,
Aourz
N,
Deneyer
L,
Bentea
E,
De Bundel
D,
Massie
A and
Smolders
IJ
(2016). Behavioral alterations occurring in the 6 Hz corneal kindling model of limbic epilepsy..
Conference Abstract:
6th Belgian Brain Congress.
doi: 10.3389/conf.fnagi.2016.03.00029
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Received:
29 Jun 2016;
Published Online:
04 Jul 2016.
*
Correspondence:
Ms. Giulia Albertini, Vrije Universiteit Brussel, Department of Pharmaceutical Chemistry and Drug Analysis, Brussels, 1090, Belgium, galberti@vub.ac.be