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Early Developmental EEG and Seizure Phenotypes in a Full Gene Deletion of Ubiquitin Protein Ligase E3A Rat Model of Angelman Syndrome

Angelman syndrome (AS) is a neurodevelopmental disorder with unique behavioral phenotypes, seizures, and distinctive electroencephalographic (EEG) patterns. Recent studies identified motor, social communication, and learning and memory deficits in a CRISPR engineered rat model with a complete matern...

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Autores principales: Born, Heather A., Martinez, Luis A., Levine, Amber T., Harris, Sarah E., Mehra, Shubhangi, Lee, Wai Ling, Dindot, Scott V., Nash, Kevin R., Silverman, Jill L., Segal, David J., Weeber, Edwin J., Anderson, Anne E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Society for Neuroscience 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114899/
https://www.ncbi.nlm.nih.gov/pubmed/33531368
http://dx.doi.org/10.1523/ENEURO.0345-20.2020
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author Born, Heather A.
Martinez, Luis A.
Levine, Amber T.
Harris, Sarah E.
Mehra, Shubhangi
Lee, Wai Ling
Dindot, Scott V.
Nash, Kevin R.
Silverman, Jill L.
Segal, David J.
Weeber, Edwin J.
Anderson, Anne E.
author_facet Born, Heather A.
Martinez, Luis A.
Levine, Amber T.
Harris, Sarah E.
Mehra, Shubhangi
Lee, Wai Ling
Dindot, Scott V.
Nash, Kevin R.
Silverman, Jill L.
Segal, David J.
Weeber, Edwin J.
Anderson, Anne E.
author_sort Born, Heather A.
collection PubMed
description Angelman syndrome (AS) is a neurodevelopmental disorder with unique behavioral phenotypes, seizures, and distinctive electroencephalographic (EEG) patterns. Recent studies identified motor, social communication, and learning and memory deficits in a CRISPR engineered rat model with a complete maternal deletion of the Ube3a gene. It is unknown whether this model recapitulates other aspects of the clinical disorder. We report here the effect of Ube3a maternal deletion in the rat on epileptiform activity, seizure threshold, and quantitative EEG. Using video-synchronized EEG (vEEG) monitoring, we assessed spectral power and epileptiform activity early postnatally through adulthood. While EEG power was similar to wild-type (WT) at 1.5 weeks postnatally, at all other ages analyzed, our findings were similar to the AS phenotype in mice and humans with significantly increased δ power. Analysis of epileptiform activity in juvenile and adult rats showed increased time spent in epileptiform activity in AS compared with WT rats. We evaluated seizure threshold using pentylenetetrazol (PTZ), audiogenic stimulus, and hyperthermia to provoke febrile seizures (FSs). Behavioral seizure scoring following PTZ induction revealed no difference in seizure threshold in AS rats, however behavioral recovery from the PTZ-induced seizure was longer in the adult group with significantly increased hippocampal epileptiform activity during this phase. When exposed to hyperthermia, AS rat pups showed a significantly lower temperature threshold to first seizure than WT. Our findings highlight an age-dependence for the EEG and epileptiform phenotypes in a preclinical model of AS, and support the use of quantitative EEG and increased δ power as a potential biomarker of AS.
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spelling pubmed-81148992021-05-12 Early Developmental EEG and Seizure Phenotypes in a Full Gene Deletion of Ubiquitin Protein Ligase E3A Rat Model of Angelman Syndrome Born, Heather A. Martinez, Luis A. Levine, Amber T. Harris, Sarah E. Mehra, Shubhangi Lee, Wai Ling Dindot, Scott V. Nash, Kevin R. Silverman, Jill L. Segal, David J. Weeber, Edwin J. Anderson, Anne E. eNeuro Research Article: New Research Angelman syndrome (AS) is a neurodevelopmental disorder with unique behavioral phenotypes, seizures, and distinctive electroencephalographic (EEG) patterns. Recent studies identified motor, social communication, and learning and memory deficits in a CRISPR engineered rat model with a complete maternal deletion of the Ube3a gene. It is unknown whether this model recapitulates other aspects of the clinical disorder. We report here the effect of Ube3a maternal deletion in the rat on epileptiform activity, seizure threshold, and quantitative EEG. Using video-synchronized EEG (vEEG) monitoring, we assessed spectral power and epileptiform activity early postnatally through adulthood. While EEG power was similar to wild-type (WT) at 1.5 weeks postnatally, at all other ages analyzed, our findings were similar to the AS phenotype in mice and humans with significantly increased δ power. Analysis of epileptiform activity in juvenile and adult rats showed increased time spent in epileptiform activity in AS compared with WT rats. We evaluated seizure threshold using pentylenetetrazol (PTZ), audiogenic stimulus, and hyperthermia to provoke febrile seizures (FSs). Behavioral seizure scoring following PTZ induction revealed no difference in seizure threshold in AS rats, however behavioral recovery from the PTZ-induced seizure was longer in the adult group with significantly increased hippocampal epileptiform activity during this phase. When exposed to hyperthermia, AS rat pups showed a significantly lower temperature threshold to first seizure than WT. Our findings highlight an age-dependence for the EEG and epileptiform phenotypes in a preclinical model of AS, and support the use of quantitative EEG and increased δ power as a potential biomarker of AS. Society for Neuroscience 2021-03-23 /pmc/articles/PMC8114899/ /pubmed/33531368 http://dx.doi.org/10.1523/ENEURO.0345-20.2020 Text en Copyright © 2021 Born et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Research Article: New Research
Born, Heather A.
Martinez, Luis A.
Levine, Amber T.
Harris, Sarah E.
Mehra, Shubhangi
Lee, Wai Ling
Dindot, Scott V.
Nash, Kevin R.
Silverman, Jill L.
Segal, David J.
Weeber, Edwin J.
Anderson, Anne E.
Early Developmental EEG and Seizure Phenotypes in a Full Gene Deletion of Ubiquitin Protein Ligase E3A Rat Model of Angelman Syndrome
title Early Developmental EEG and Seizure Phenotypes in a Full Gene Deletion of Ubiquitin Protein Ligase E3A Rat Model of Angelman Syndrome
title_full Early Developmental EEG and Seizure Phenotypes in a Full Gene Deletion of Ubiquitin Protein Ligase E3A Rat Model of Angelman Syndrome
title_fullStr Early Developmental EEG and Seizure Phenotypes in a Full Gene Deletion of Ubiquitin Protein Ligase E3A Rat Model of Angelman Syndrome
title_full_unstemmed Early Developmental EEG and Seizure Phenotypes in a Full Gene Deletion of Ubiquitin Protein Ligase E3A Rat Model of Angelman Syndrome
title_short Early Developmental EEG and Seizure Phenotypes in a Full Gene Deletion of Ubiquitin Protein Ligase E3A Rat Model of Angelman Syndrome
title_sort early developmental eeg and seizure phenotypes in a full gene deletion of ubiquitin protein ligase e3a rat model of angelman syndrome
topic Research Article: New Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114899/
https://www.ncbi.nlm.nih.gov/pubmed/33531368
http://dx.doi.org/10.1523/ENEURO.0345-20.2020
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