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@ARTICLE{Merseburg:165144,
      author       = {Merseburg, Andrea and Kasemir, Jacquelin and Buss, Eric W
                      and Leroy, Felix and Bock, Tobias and Porro, Alessandro and
                      Barnett, Anastasia and Tröder, Simon E and Engeland, Birgit
                      and Stockebrand, Malte and Moroni, Anna and Siegelbaum,
                      Steve and Isbrandt, Dirk and Santoro, Bina},
      title        = {{S}eizures, behavioral deficits and adverse drug responses
                      in two new genetic mouse models of {HCN}1 epileptic
                      encephalopathy.},
      journal      = {eLife},
      volume       = {11},
      issn         = {2050-084X},
      address      = {Cambridge},
      publisher    = {eLife Sciences Publications},
      reportid     = {DZNE-2022-01449},
      pages        = {e70826},
      year         = {2022},
      note         = {CC BY: https://creativecommons.org/licenses/by/4.0/},
      abstract     = {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 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 effect to further impair 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 towards reaching this objective.},
      keywords     = {Animals / Anticonvulsants / Brain Diseases: genetics /
                      Child / Humans / Hyperpolarization-Activated Cyclic
                      Nucleotide-Gated Channels: genetics / Lamotrigine /
                      Ligand-Gated Ion Channels / Mice / Phenytoin / Potassium
                      Channels: genetics / Seizures: drug therapy / Seizures:
                      genetics / mouse (Other) / neuroscience (Other)},
      cin          = {AG Isbrandt},
      ddc          = {600},
      cid          = {I:(DE-2719)1011003},
      pnm          = {351 - Brain Function (POF4-351)},
      pid          = {G:(DE-HGF)POF4-351},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC9481245},
      pubmed       = {pmid:35972069},
      doi          = {10.7554/eLife.70826},
      url          = {https://pub.dzne.de/record/165144},
}