Inhibitory G-protein Modulation of CNS Excitability.

Abstract

Epilepsy represents a major health burden upon society. Approximately 30% of patients still remain symptomatic despite therapy. While not a current medicinal target for epilepsy, the family of inhibitory G-proteins appears to play an important role in this disease, as blocking their function in animal models increases both acute seizure susceptibility and the rate of spontaneous seizure development in kindling, a research model with parallels to epilepsy. The most abundant inhibitory G-protein in the brain is Go, composing roughly 2% of membrane bound protein. To further clarify the role of Go in epilepsy a Gnao1 gain-of-function mouse line (RGSi/G184S) was employed. Hippocampal slices from Gnao1 +/RGSi mice show enhanced epinephrine-mediated suppression of epileptiform burst firing of neurons demonstrating that Gnao1 +/RGSi mice have enhanced Go signaling. The aforementioned work lead me to hypothesize that C57BL/6J Gnao1 +/RGSi mice would be protected from kindling. In fact, the mice experience premature death, enhanced kindling susceptibility and over a ten-fold increase in frequency of electrical disturbances within their brain. C57BL/6J Gnao1 +/RGSi mice also display an unexpected loss of inhibitory signaling within specific brain regions. Interestingly, the mutation is only lethal on the C57BL/6J background. The progenitor 129S1/SvImJ strain demonstrates no change in seizure susceptibility or viability. A genome-wide SNP analysis identified a region on chromosome 17 between 41-70 megabases that affords protection from spontaneous lethality. Further, this region also reduces the rate at which mice develop seizures in response to kindling. This region was further refined to a subregion from 41-51 megabases which was found sufficient to afford protection to kindling. Consequently, I have identified two genomic loci, Gnao1 and the Chr17 modifier which I term Mogs1 (modifier of G-protein seizures), that should be examined as candidates in human epilepsy. Additionally, future use of this model should prove informative in assessing the utility of novel therapeutics to prevent the progression of epilepsy.