Home > Publications Database > Seizures, behavioral deficits and adverse drug responses in two new genetic mouse models of HCN1 epileptic encephalopathy. > print

001     165144
005     20230915090607.0
024 7 _ |a pmc:PMC9481245
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037 _ _ |a DZNE-2022-01449
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100 1 _ |a Merseburg, Andrea
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245 _ _ |a Seizures, behavioral deficits and adverse drug responses in two new genetic mouse models of HCN1 epileptic encephalopathy.
260 _ _ |a Cambridge
|c 2022
|b eLife Sciences Publications
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500 _ _ |a CC BY: https://creativecommons.org/licenses/by/4.0/
520 _ _ |a 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.
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650 _ 7 |a mouse
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650 _ 7 |a neuroscience
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650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Anticonvulsants
|2 MeSH
650 _ 2 |a Brain Diseases: genetics
|2 MeSH
650 _ 2 |a Child
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels: genetics
|2 MeSH
650 _ 2 |a Lamotrigine
|2 MeSH
650 _ 2 |a Ligand-Gated Ion Channels
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650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a Phenytoin
|2 MeSH
650 _ 2 |a Potassium Channels: genetics
|2 MeSH
650 _ 2 |a Seizures: drug therapy
|2 MeSH
650 _ 2 |a Seizures: genetics
|2 MeSH
700 1 _ |a Kasemir, Jacquelin
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700 1 _ |a Buss, Eric W
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700 1 _ |a Leroy, Felix
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700 1 _ |a Bock, Tobias
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700 1 _ |a Porro, Alessandro
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700 1 _ |a Barnett, Anastasia
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700 1 _ |a Tröder, Simon E
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700 1 _ |a Engeland, Birgit
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700 1 _ |a Stockebrand, Malte
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700 1 _ |a Moroni, Anna
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700 1 _ |a Siegelbaum, Steve
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700 1 _ |a Isbrandt, Dirk
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700 1 _ |a Santoro, Bina
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773 _ _ |a 10.7554/eLife.70826
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856 4 _ |y OpenAccess
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