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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 Synd...

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Published in:PLoS genetics 2015-06, Vol.11 (6), p.e1005347
Main Authors: Asinof, Samuel K, Sukoff Rizzo, Stacey J, Buckley, Alexandra R, Beyer, Barbara J, Letts, Verity A, Frankel, Wayne N, Boumil, Rebecca M
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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. Dnm1Ftfl 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 Dnm1Ftfl mouse model of DNM1 EE. Observations of Dnm1Ftfl/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.
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subjects Amphetamines
Animal cognition
Animals
Behavior
Behavior, Animal
Convulsions & seizures
Disease Models, Animal
Dynamin I - genetics
Dynamin I - metabolism
Electroencephalography
Epilepsy
Epilepsy - epidemiology
Epilepsy - genetics
Epilepsy - mortality
Epilepsy - pathology
Female
Gene Deletion
Humans
Infant
Lennox Gastaut Syndrome - epidemiology
Lennox Gastaut Syndrome - genetics
Male
Mice, Mutant Strains
Mutation
Neurons - pathology
Phenotype
Prosencephalon - metabolism
Prosencephalon - physiopathology
Proteins
Rodents
Spasms, Infantile - epidemiology
Spasms, Infantile - genetics
Studies
Synaptic Transmission
title Independent Neuronal Origin of Seizures and Behavioral Comorbidities in an Animal Model of a Severe Childhood Genetic Epileptic Encephalopathy
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