Presenting Author:
Principal Investigator:
Department:
Pharmacology
Keywords:
Ion channel, epilepsy, Dravet syndrome, sodium channel, calcium channel, modifier gene
Location:
Third Floor, Feinberg Pavilion, Northwestern Memorial Hospital
B152 - Basic Science
Cacna1g modifies epilepsy in a mouse model of Dravet syndrome
Rationale: Epilepsy is a common neurological disorder characterized by recurrent seizures, periods of rampant electrical activity in the brain. Mutations in genes encoding voltage-gated sodium channels are responsible for several types of human epilepsy. More than 1200 mutations in the neuronal sodium channels SCN1A and SCN2A have been identified in patients with several epilepsy syndromes, including Genetic Epilepsy with Febrile Seizures Plus, Dravet Syndrome (DS), and Benign Familial Neonatal-Infantile Seizures. A common feature of genetic epilepsies is variable expressivity in individuals with the same mutation. We generated mouse models with mutations in voltage-gated sodium channels Scn1a and Scn2a and seizure-related phenotypes with different underlying mechanisms. Both of these mouse models show strain-dependent phenotype severity. These observations demonstrate that genetic modifiers act to influence the expressivity of epilepsy. Cacna1g, encoding the Cav3.1 voltage-gated calcium channel subunit, was identified as a candidate modifier of epilepsy in the Scn2aQ54 mouse model using genetic mapping and RNA-seq transcriptome analysis. We recently reported altered spontaneous seizure frequency in Scn2aQ54/+ mice with transgenic alteration of Cacna1g expression, in support of our hypothesis that Cacna1g is a genetic modifier of epilepsy. In this study, transgenic strategies were used to increase or decrease the expression of Cacna1g to test the hypothesis that altered Cacna1g expression would affect severity of the epilepsy phenotype in the Scn1aKO/+ mouse model of DS. Methods: Transgenesis was utilized to elevate Cacna1g expression (B6.Cacna1gHIGH or B6.1GH). The B6.1GH line was crossed with the Scn1aKO/+ line (129.1AKO/+) to generate a phenotyping cohort. We used a global Cacna1g knockout strain (B6.1GKO/+) to reduce Cacna1g expression. The B6.1GKO/+ line was crossed with the Scn1aKO/+ line to generate a phenotyping cohort. Single and double transgenic littermates were phenotyped to assess longevity, spontaneous seizure frequency, and febrile seizure susceptibility. Results: We observed no effect of elevated Cacna1g on any phenotype measures in the DS model. In contrast, reduced Cacna1g expression resulted in partial amelioration of DS phenotype measures. Specifically, reduced Cacna1g expression results in increased survival and reduced spontaneous seizure frequency. Conclusions: We provide evidence that reduced Cacna1g expression results in partial rescue of the DS epilepsy phenotype. These results support Cacna1g as a genetic modifier of DS. Further, we propose Cacna1g as a potential therapeutic target for epilepsy. The identification of modifiers that influence susceptibility and disease progression will provide insight into the etiology of epilepsy and suggest novel therapies for improved treatment of human patients.
