TY - JOUR TI - Seizures, behavioral deficits, and adverse drug responses in two new genetic mouse models of HCN1 epileptic encephalopathy AU - Merseburg, Andrea AU - Kasemir, Jacquelin AU - Buss, Eric W AU - Leroy, Felix AU - Bock, Tobias AU - Porro, Alessandro AU - Barnett, Anastasia AU - Tröder, Simon E AU - Engeland, Birgit AU - Stockebrand, Malte AU - Moroni, Anna AU - Siegelbaum, Steven A AU - Isbrandt, Dirk AU - Santoro, Bina A2 - Chetkovich, Dane M A2 - Huguenard, John R A2 - Chetkovich, Dane M A2 - Baram, Tallie Z VL - 11 PY - 2022 DA - 2022/08/16 SP - e70826 C1 - eLife 2022;11:e70826 DO - 10.7554/eLife.70826 UR - https://doi.org/10.7554/eLife.70826 AB - De novo mutations in voltage- and ligand-gated channels have been associated with an increasing number of cases of developmental and epileptic encephalopathies, which often fail to respond to classic antiseizure medications. Here, we examine two knock-in mouse models replicating de novo sequence variations in the human HCN1 voltage-gated channel gene, p.G391D and p.M153I (Hcn1G380D/+ and Hcn1M142I/+ in mouse), associated with severe drug-resistant neonatal- and childhood-onset epilepsy, respectively. Heterozygous mice from both lines displayed spontaneous generalized tonic–clonic seizures. Animals replicating the p.G391D variant had an overall more severe phenotype, with pronounced alterations in the levels and distribution of HCN1 protein, including disrupted targeting to the axon terminals of basket cell interneurons. In line with clinical reports from patients with pathogenic HCN1 sequence variations, administration of the antiepileptic Na+ channel antagonists lamotrigine and phenytoin resulted in the paradoxical induction of seizures in both mouse lines, consistent with an impairment in inhibitory neuron function. We also show that these variants can render HCN1 channels unresponsive to classic antagonists, indicating the need to screen mutated channels to identify novel compounds with diverse mechanism of action. Our results underscore the necessity of tailoring effective therapies for specific channel gene variants, and how strongly validated animal models may provide an invaluable tool toward reaching this objective. KW - HCN1 KW - ion channels KW - epileptic encephalopathy KW - lamotrigine KW - phenytoin KW - Dravet syndrome JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -