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Seizures, behavioral deficits, and adverse drug responses in two new genetic mouse models of HCN1 epileptic encephalopathy

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 var...

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Autores principales: Merseburg, Andrea, Kasemir, Jacquelin, Buss, Eric W, Leroy, Felix, Bock, Tobias, Porro, Alessandro, Barnett, Anastasia, Tröder, Simon E, Engeland, Birgit, Stockebrand, Malte, Moroni, Anna, Siegelbaum, Steven A, Isbrandt, Dirk, Santoro, Bina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9481245/
https://www.ncbi.nlm.nih.gov/pubmed/35972069
http://dx.doi.org/10.7554/eLife.70826
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author Merseburg, Andrea
Kasemir, Jacquelin
Buss, Eric W
Leroy, Felix
Bock, Tobias
Porro, Alessandro
Barnett, Anastasia
Tröder, Simon E
Engeland, Birgit
Stockebrand, Malte
Moroni, Anna
Siegelbaum, Steven A
Isbrandt, Dirk
Santoro, Bina
author_facet Merseburg, Andrea
Kasemir, Jacquelin
Buss, Eric W
Leroy, Felix
Bock, Tobias
Porro, Alessandro
Barnett, Anastasia
Tröder, Simon E
Engeland, Birgit
Stockebrand, Malte
Moroni, Anna
Siegelbaum, Steven A
Isbrandt, Dirk
Santoro, Bina
author_sort Merseburg, Andrea
collection PubMed
description 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 (Hcn1(G380D/+) and Hcn1(M142I/+) 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.
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spelling pubmed-94812452022-09-17 Seizures, behavioral deficits, and adverse drug responses in two new genetic mouse models of HCN1 epileptic encephalopathy Merseburg, Andrea Kasemir, Jacquelin Buss, Eric W Leroy, Felix Bock, Tobias Porro, Alessandro Barnett, Anastasia Tröder, Simon E Engeland, Birgit Stockebrand, Malte Moroni, Anna Siegelbaum, Steven A Isbrandt, Dirk Santoro, Bina eLife Neuroscience 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 (Hcn1(G380D/+) and Hcn1(M142I/+) 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. eLife Sciences Publications, Ltd 2022-08-16 /pmc/articles/PMC9481245/ /pubmed/35972069 http://dx.doi.org/10.7554/eLife.70826 Text en © 2022, Merseburg et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Neuroscience
Merseburg, Andrea
Kasemir, Jacquelin
Buss, Eric W
Leroy, Felix
Bock, Tobias
Porro, Alessandro
Barnett, Anastasia
Tröder, Simon E
Engeland, Birgit
Stockebrand, Malte
Moroni, Anna
Siegelbaum, Steven A
Isbrandt, Dirk
Santoro, Bina
Seizures, behavioral deficits, and adverse drug responses in two new genetic mouse models of HCN1 epileptic encephalopathy
title Seizures, behavioral deficits, and adverse drug responses in two new genetic mouse models of HCN1 epileptic encephalopathy
title_full Seizures, behavioral deficits, and adverse drug responses in two new genetic mouse models of HCN1 epileptic encephalopathy
title_fullStr Seizures, behavioral deficits, and adverse drug responses in two new genetic mouse models of HCN1 epileptic encephalopathy
title_full_unstemmed Seizures, behavioral deficits, and adverse drug responses in two new genetic mouse models of HCN1 epileptic encephalopathy
title_short Seizures, behavioral deficits, and adverse drug responses in two new genetic mouse models of HCN1 epileptic encephalopathy
title_sort seizures, behavioral deficits, and adverse drug responses in two new genetic mouse models of hcn1 epileptic encephalopathy
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9481245/
https://www.ncbi.nlm.nih.gov/pubmed/35972069
http://dx.doi.org/10.7554/eLife.70826
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