Characterization and application of hyperthermia-evoked seizures in a mouse model of focal cortical dysplasia

Zhang, X.; Rana, C.; Shen, R.; Yang, T.; Barden, J.; Haberland, H.; Jiang, M.; Qureshi, R.; Siddiqui, S.; Sajdak, A.; Lawlor, P.; Wang, Y.; Mattis, J.

doi:10.64898/2025.12.19.695581

bioRxiv · 10.64898/2025.12.19.695581

Characterization and application of hyperthermia-evoked seizures in a mouse model of focal cortical dysplasia

Zhang, X.·Rana, C.·Shen, R.·Yang, T.·Barden, J.·Haberland, H.·Jiang, M.·Qureshi, R.·Siddiqui, S.·Sajdak, A.·Lawlor, P.·Wang, Y.·Mattis, J.

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Abstract

Rodent models of drug-resistant epilepsy are widely used to uncover mechanisms of seizures and to test the efficacy of treatments; however, the stochastic and relatively infrequent nature of spontaneous seizures in these models makes it challenging to observe and manipulate peri-ictal activity, and to rapidly screen therapeutics. As fever has been identified as a clinical seizure trigger, we investigated the ability of induced hyperthermia to trigger seizures in a mouse model of focal cortical dysplasia (FCD), a common cause of drug-resistant epilepsy. Experimental mice were generated via in utero electroporation of a gain-of-function RHEB variant (RHEBp.P37L). In adult Rheb-FCD mice, hyperthermia elicited behavioral seizures [~]80% of the time, with a mean temperature threshold of [~]40 {degrees}C. Using this acute paradigm, as a proof-of-concept, we found that chemogenetic inhibition of a subset of excitatory neurons within the dysplasia significantly elevated the threshold for hyperthermia-evoked seizures. We then confirmed the relevance of this acute finding to spontaneous epileptiform activity, using repeated chemogenetic inhibition across chronic recordings to confirm a reduction of spontaneous seizures as well as interictal spikes. Overall, our data demonstrate that hyperthermia-evoked seizures can be readily elicited in Rheb-FCD mice, offering a tractable platform for evaluating therapeutic interventions targeting seizure susceptibility in focal epilepsy.

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Zhang, X., Rana, C., Shen, R., Yang, T., Barden, J., Haberland, H., Jiang, M., Qureshi, R., Siddiqui, S., Sajdak, A., Lawlor, P., Wang, Y., Mattis, J.. 2025-12-22. Characterization and application of hyperthermia-evoked seizures in a mouse model of focal cortical dysplasia. https://doi.org/10.64898/2025.12.19.695581

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