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Independent Neuronal Origin of Seizures and Behavioral Comorbidities in an Animal Model of a Severe Childhood Genetic Epileptic Encephalopathy
The childhood epileptic encephalopathies (EE’s) are seizure disorders that broadly impact development including cognitive, sensory and motor progress with severe consequences and comorbidities. Recently, mutations in DNM1 (dynamin 1) have been implicated in two EE syndromes, Lennox-Gastaut Syndrome...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Public Library of Science
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4488318/ https://www.ncbi.nlm.nih.gov/pubmed/26125563 http://dx.doi.org/10.1371/journal.pgen.1005347 |
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author | Asinof, Samuel K. Sukoff Rizzo, Stacey J. Buckley, Alexandra R. Beyer, Barbara J. Letts, Verity A. Frankel, Wayne N. Boumil, Rebecca M. |
author_facet | Asinof, Samuel K. Sukoff Rizzo, Stacey J. Buckley, Alexandra R. Beyer, Barbara J. Letts, Verity A. Frankel, Wayne N. Boumil, Rebecca M. |
author_sort | Asinof, Samuel K. |
collection | PubMed |
description | The childhood epileptic encephalopathies (EE’s) are seizure disorders that broadly impact development including cognitive, sensory and motor progress with severe consequences and comorbidities. Recently, mutations in DNM1 (dynamin 1) have been implicated in two EE syndromes, Lennox-Gastaut Syndrome and Infantile Spasms. Dnm1 encodes dynamin 1, a large multimeric GTPase necessary for activity-dependent membrane recycling in neurons, including synaptic vesicle endocytosis. Dnm1(Ftfl) or “fitful” mice carry a spontaneous mutation in the mouse ortholog of DNM1 and recapitulate many of the disease features associated with human DNM1 patients, providing a relevant disease model of human EE’s. In order to examine the cellular etiology of seizures and behavioral and neurological comorbidities, we engineered a conditional Dnm1(Ftfl) mouse model of DNM1 EE. Observations of Dnm1 (Ftfl/flox) mice in combination with various neuronal subpopulation specific cre strains demonstrate unique seizure phenotypes and clear separation of major neurobehavioral comorbidities from severe seizures associated with the germline model. This demonstration of pleiotropy suggests that treating seizures per se may not prevent severe comorbidity observed in EE associated with dynamin-1 mutations, and is likely to have implications for other genetic forms of EE. |
format | Online Article Text |
id | pubmed-4488318 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-44883182015-07-02 Independent Neuronal Origin of Seizures and Behavioral Comorbidities in an Animal Model of a Severe Childhood Genetic Epileptic Encephalopathy Asinof, Samuel K. Sukoff Rizzo, Stacey J. Buckley, Alexandra R. Beyer, Barbara J. Letts, Verity A. Frankel, Wayne N. Boumil, Rebecca M. PLoS Genet Research Article The childhood epileptic encephalopathies (EE’s) are seizure disorders that broadly impact development including cognitive, sensory and motor progress with severe consequences and comorbidities. Recently, mutations in DNM1 (dynamin 1) have been implicated in two EE syndromes, Lennox-Gastaut Syndrome and Infantile Spasms. Dnm1 encodes dynamin 1, a large multimeric GTPase necessary for activity-dependent membrane recycling in neurons, including synaptic vesicle endocytosis. Dnm1(Ftfl) or “fitful” mice carry a spontaneous mutation in the mouse ortholog of DNM1 and recapitulate many of the disease features associated with human DNM1 patients, providing a relevant disease model of human EE’s. In order to examine the cellular etiology of seizures and behavioral and neurological comorbidities, we engineered a conditional Dnm1(Ftfl) mouse model of DNM1 EE. Observations of Dnm1 (Ftfl/flox) mice in combination with various neuronal subpopulation specific cre strains demonstrate unique seizure phenotypes and clear separation of major neurobehavioral comorbidities from severe seizures associated with the germline model. This demonstration of pleiotropy suggests that treating seizures per se may not prevent severe comorbidity observed in EE associated with dynamin-1 mutations, and is likely to have implications for other genetic forms of EE. Public Library of Science 2015-06-30 /pmc/articles/PMC4488318/ /pubmed/26125563 http://dx.doi.org/10.1371/journal.pgen.1005347 Text en © 2015 Asinof et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Asinof, Samuel K. Sukoff Rizzo, Stacey J. Buckley, Alexandra R. Beyer, Barbara J. Letts, Verity A. Frankel, Wayne N. Boumil, Rebecca M. Independent Neuronal Origin of Seizures and Behavioral Comorbidities in an Animal Model of a Severe Childhood Genetic Epileptic Encephalopathy |
title | Independent Neuronal Origin of Seizures and Behavioral Comorbidities in an Animal Model of a Severe Childhood Genetic Epileptic Encephalopathy |
title_full | Independent Neuronal Origin of Seizures and Behavioral Comorbidities in an Animal Model of a Severe Childhood Genetic Epileptic Encephalopathy |
title_fullStr | Independent Neuronal Origin of Seizures and Behavioral Comorbidities in an Animal Model of a Severe Childhood Genetic Epileptic Encephalopathy |
title_full_unstemmed | Independent Neuronal Origin of Seizures and Behavioral Comorbidities in an Animal Model of a Severe Childhood Genetic Epileptic Encephalopathy |
title_short | Independent Neuronal Origin of Seizures and Behavioral Comorbidities in an Animal Model of a Severe Childhood Genetic Epileptic Encephalopathy |
title_sort | independent neuronal origin of seizures and behavioral comorbidities in an animal model of a severe childhood genetic epileptic encephalopathy |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4488318/ https://www.ncbi.nlm.nih.gov/pubmed/26125563 http://dx.doi.org/10.1371/journal.pgen.1005347 |
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