Rebecca Boumil, Ph.D.

Senior Study Director

Investigating the genetics underlying epileptic seizures using mouse models of the disease.

Our lab studies the “fitful” mouse as a model of generalized idiopathic epilepsy. Fitful mice carry a spontaneous mutation in the Dnm1 gene, which we described in 2010. Disruption of dynamin function in mice impairs SV endocytosis, with a more dramatic effect during high levels of neuronal activity. Heterozygous mice develop spontaneous and handling-induced seizures at 2 to 3 months of age, but otherwise appear normal. Homozygous mice have a more severe phenotype, including seizures that often lead to death before weaning age, ataxia and neurosensory defects, highlighting the importance of synaptic vesicle recycling in the brain.

Recently, human patients have been identified with mutations in DNM1. These patients all have very severe early epileptic encephalopathies and present early in life with seizures, developmental delay and intellectual decline among other comorbid issues. Currently, we are employing the Dnm1ftfl and conditional Dnm1null alleles to create inducible genetic models that do not exhibit these polymorphic comorbid effects. Preliminary observations of Dnm1ftfl/flox mice in combination with various neuronal subpopulation-specific Cre strains have demonstrated unique seizure phenotypes. These results suggest the possibility that the behavioral comorbidities may be separate from the seizures and that the gene defect may be pleiotropic in different neuron types.

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