Stiftung Tierärztliche Hochschule Hannover (TiHo)

A face-to-face comparison of the intra-amygdala and intrahippocampal kainate mouse models of mesial temporal lobe epilepsy and their utility for testing novel therapies

Welzel, Lisa GND; Schidlitzki, Alina GND; Twele, Friederike GND; Anjum, Syed Muhammad Muneeb ORCID; Löscher, Wolfgang GND

OBJECTIVE:Intracranial (intrahippocampal or intra-amygdala) administration of kainate in rodents leads to spatially restricted brain injury and development of focal epilepsy with characteristics that resemble mesial temporal lobe epilepsy. Such rodent models are used both in the search for more effective antiseizure drugs (ASDs) and in the development of antiepileptogenic strategies. However, it is not clear which of the models is best suited for testing different types of epilepsy therapies. METHODS:In the present study, we performed a face-to-face comparison of the intra-amygdala kainate (IAK) and intrahippocampal kainate (IHK) mouse models using the same mouse inbred strain (C57BL/6). For comparison, some experiments were performed in mouse outbred strains. RESULTS:Intra-amygdala kainate injection led to more severe status epilepticus and higher mortality than intrahippocampal injection. In male C57BL/6 mice, the latent period to spontaneous recurrent seizures (SRSs) was short or absent in both models, whereas a significantly longer latent period was determined in NMRI and CD-1 outbred mice. When SRSs were recorded from the ipsilateral hippocampus, relatively frequent electroclinical seizures were determined in the IAK model, whereas only infrequent electroclinical seizures but extremely frequent focal electrographic seizures were determined in the IHK model. As a consequence of the differences in SRS frequency, prolonged video-electroencephalographic monitoring and drug administration were needed for testing efficacy of the benchmark ASD carbamazepine in the IAK model, whereas acute drug testing was possible in the IHK model. In both models, carbamazepine was only effective at high doses, indicating ASD resistance to this benchmark drug. SIGNIFICANCE:We found a variety of significant differences between the IAK and IHK models, which are important when deciding which of these models is best suited for studies on novel epilepsy therapies. The IAK model appears particularly interesting for studies on disease-modifying treatments, whereas the IHK model is well suited for studying the antiseizure activity of novel ASDs against difficult-to-treated focal seizures.

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Welzel, L., Schidlitzki, A., Twele, F., Anjum, M., Löscher, W., 2020. A face-to-face comparison of the intra-amygdala and intrahippocampal kainate mouse models of mesial temporal lobe epilepsy and their utility for testing novel therapies. Epilepsia 61, 157–170. https://doi.org/10.1111/epi.16406
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