Cargando…
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...
Autores principales: | , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1784791221355413504 |
---|---|
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. |
format | Online Article Text |
id | pubmed-9481245 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT merseburgandrea seizuresbehavioraldeficitsandadversedrugresponsesintwonewgeneticmousemodelsofhcn1epilepticencephalopathy AT kasemirjacquelin seizuresbehavioraldeficitsandadversedrugresponsesintwonewgeneticmousemodelsofhcn1epilepticencephalopathy AT bussericw seizuresbehavioraldeficitsandadversedrugresponsesintwonewgeneticmousemodelsofhcn1epilepticencephalopathy AT leroyfelix seizuresbehavioraldeficitsandadversedrugresponsesintwonewgeneticmousemodelsofhcn1epilepticencephalopathy AT bocktobias seizuresbehavioraldeficitsandadversedrugresponsesintwonewgeneticmousemodelsofhcn1epilepticencephalopathy AT porroalessandro seizuresbehavioraldeficitsandadversedrugresponsesintwonewgeneticmousemodelsofhcn1epilepticencephalopathy AT barnettanastasia seizuresbehavioraldeficitsandadversedrugresponsesintwonewgeneticmousemodelsofhcn1epilepticencephalopathy AT trodersimone seizuresbehavioraldeficitsandadversedrugresponsesintwonewgeneticmousemodelsofhcn1epilepticencephalopathy AT engelandbirgit seizuresbehavioraldeficitsandadversedrugresponsesintwonewgeneticmousemodelsofhcn1epilepticencephalopathy AT stockebrandmalte seizuresbehavioraldeficitsandadversedrugresponsesintwonewgeneticmousemodelsofhcn1epilepticencephalopathy AT moronianna seizuresbehavioraldeficitsandadversedrugresponsesintwonewgeneticmousemodelsofhcn1epilepticencephalopathy AT siegelbaumstevena seizuresbehavioraldeficitsandadversedrugresponsesintwonewgeneticmousemodelsofhcn1epilepticencephalopathy AT isbrandtdirk seizuresbehavioraldeficitsandadversedrugresponsesintwonewgeneticmousemodelsofhcn1epilepticencephalopathy AT santorobina seizuresbehavioraldeficitsandadversedrugresponsesintwonewgeneticmousemodelsofhcn1epilepticencephalopathy |