Universität zu Köln

Merseburg, Andrea ORCID: 0000-0003-0630-6564, Kasemir, Jacquelin, Buss, Eric W., Leroy, Felix, Bock, Tobias ORCID: 0000-0002-7734-1183, Porro, Alessandro ORCID: 0000-0003-4845-6165, Barnett, Anastasia, Troder, Simon E., Engeland, Birgit, Stockebrand, Malte, Moroni, Anna, Siegelbaum, Steven A., Isbrandt, Dirk ORCID: 0000-0002-4720-1016 and Santoro, Bina (2022). Seizures, behavioral deficits, and adverse drug responses in two new genetic mouse models of HCN1 epileptic encephalopathy. eLife, 11. CAMBRIDGE: eLIFE SCIENCES PUBL LTD. ISSN 2050-084X

Full text not available from this repository.

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 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Merseburg, Andrea UNSPECIFIED orcid.org/0000-0003-0630-6564 UNSPECIFIED Kasemir, Jacquelin UNSPECIFIED UNSPECIFIED UNSPECIFIED Buss, Eric W. UNSPECIFIED UNSPECIFIED UNSPECIFIED Leroy, Felix UNSPECIFIED UNSPECIFIED UNSPECIFIED Bock, Tobias UNSPECIFIED orcid.org/0000-0002-7734-1183 UNSPECIFIED Porro, Alessandro UNSPECIFIED orcid.org/0000-0003-4845-6165 UNSPECIFIED Barnett, Anastasia UNSPECIFIED UNSPECIFIED UNSPECIFIED Troder, Simon E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Engeland, Birgit UNSPECIFIED UNSPECIFIED UNSPECIFIED Stockebrand, Malte UNSPECIFIED UNSPECIFIED UNSPECIFIED Moroni, Anna UNSPECIFIED UNSPECIFIED UNSPECIFIED Siegelbaum, Steven A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Isbrandt, Dirk UNSPECIFIED orcid.org/0000-0002-4720-1016 UNSPECIFIED Santoro, Bina UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-680295
DOI:	10.7554/eLife.70826
Journal or Publication Title:	eLife
Volume:	11
Date:	2022
Publisher:	eLIFE SCIENCES PUBL LTD
Place of Publication:	CAMBRIDGE
ISSN:	2050-084X
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language HYPERPOLARIZATION-ACTIVATED CURRENT; I-H; PYRAMIDAL NEURONS; DISTAL DENDRITES; CATION CHANNELS; DENTATE GYRUS; SUBUNITS; MICE; INTERNEURONS; EXCITABILITY Multiple languages Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/68029