Abstracts

Rationale: The SCN1B(C121W) mutation is described in an Australian family with generalised epilepsy with febrile seizures + (GEFS+). We have developed mice that harbour the C121W mutation in order to investigate cellular and network mechanisms underlying this disease. Methods: EEG recordings were made from epidural electrodes. Thermal seizures were induced by a hot stream of air during which body temperature was measured rectally. Acute slices were cut from P14 animals. Whole-cell recordings were made in current clamp mode from CA1 pyramidal and inhibitory neurons. Results: The phenotype of homozygous mice is severe leading to premature death by approximately age P20. The mice have aberrant EEGs consistent with seizure activity. Mice also display an ataxic gait. Further, a thermal insult results in seizures at a lower temperature threshold than wild type mice. Thermal-mediated seizures are distinct in their expression, involving full tonic-clonic seizures for mutant mice that are never observed in wild type. Single-cell electrophysiological measurements revealed a deficit in the CA1 region of the hippocampus. An input-output relationship that measures action potential (AP) firing with progressively larger current injections in pyramidal neurons shows a collapse of AP trains at higher current injections. This collapse was not evident for inhibitory interneurons. Conclusions: Homozygous C121W mice display several of the key behavioural phenotypes noted in Scn1a mutant mice models of Dravet syndrome. We extend this to include a more severe febrile seizure phenotype. In contrast to Scn1a mouse models AP collapse occur in pyramidal neurons and not inhibitory interneurons. These results are particularly interesting in the context of the recently described patient with Dravet syndrome who is homozygous for the SCN1B(R125C) mutation.