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

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 °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 predictive validity of this acute finding, employing 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. • Hyperthermia reliably evokes seizures in a mouse model of focal cortical dysplasia. • Neurons within the dysplasia are activated by hyperthermia-evoked seizures. • Inhibiting excitatory neurons within the dysplasia protects against evoked seizures. • The same intervention similarly protects against spontaneous seizures and spikes. • Hyperthermia-evoked seizures offer a higher-throughput screening platform.