An inducible model of a human epilepsy mutation

An inducible model of a human epilepsy mutation

In this project, we created and validated a novel mouse model in which we can temporally control the expression of a human epilepsy mutation.  To do this, we used a "gene silencing" Neomycin resistance cassette which normally suppresses the expression of the mutation, however, with the use of a drug called doxycycline, we can switch on the mutation by in vivo excision of the silencing Neomycin cassette.  The mutation is in the GABA receptor gene which has major impact during brain development as well as playing an important direct inhibitory role in the adult brain.  By expressing the mutation after brain development has completed, we have addressed a central issue of epilepsy genetics which is whether epilepsy gene mutations cause epilepsy by perturbing brain development or they directly impact brain function to result in seizures.  So far, we have preliminary evidence that the mutation has developmental effects which worsen seizures later in life.  More work is currently under progress to study the possible developmental effects of this mutation.  Other uses of this model include expressing the mutation in different cell types in the CNS to determine the neuronal components that drive seizure phenotypes.  With the creation of this novel model, we now have the ability to gain precise control over temporal and spatial aspects of epilepsy gene expression.