Efficacy of antiseizure medication in a mouse model of HCN1 developmental and epileptic encephalopathy


Acquisition of drug-sensitivity profiles is challenging in rare epilepsies. Anecdotal evidence suggests that antiseizure medications that block sodium channels as their primary mechanism of action exacerbate seizures in HCN1 developmental and epileptic encephalopathies (DEEs), whereas sodium valproate is effective for some patients. The Hcn1 M294L heterozygous knock-in (Hcn1M294L) mouse carries the homologue of the recurrent gain-of-function HCN1 M305L pathogenic variant and recapitulates the seizure and some behavioral phenotypes observed in patients. We used this mouse model to study drug efficacy in HCN1 DEE. Hcn1M294L mice display epileptiform spiking on electrocorticography (ECoG), which we used as a quantifiable measure of drug effect. Phenytoin, lamotrigine, and retigabine significantly increased ECoG spike frequency, with lamotrigine and retigabine triggering seizures in a subset of the mice tested. In addition, there was a strong trend for carbamazepine to increase spiking. In contrast, levetiracetam, diazepam, sodium valproate, and ethosuximide all significantly reduced ECoG spike frequency. Drugs that reduced spiking did not cause any consistent ECoG spectral changes, whereas drugs that increased spiking all increased power in the slower delta and/or theta bands. These data provide a framework on which to build our understanding of gain-of-function HCN1 DEE pharmacosensitivity in the clinical setting.