Abstracts

Rationale. Mutations which slow the rate of inactivation in muscle and cardiac voltage-gated sodium channels result in human disease. We sought to determine the in vivo effect of such a mutation in a neuronal voltage-gated sodium channel. Methods. The neuron-specific enolase promoter was used to direct expression of a rat brain IIA sodium channel with a site directed mutation of residues 879-881 in the S4/S5 linker of domain 2. This mutation, designated 2AQ3, results in a reduced rate of inactivation and increased persistent current in Xenopus oocytes. Results. 2AQ3 mice exhibited seizures with behavioral arrest and stereotyped behaviors beginning at one month of age. Continuous EEG monitoring detected focal seizure activity in the hippocampus. As the mice age, seizures become more frequent and generalize to involve the cortex, leading to premature death. Hippocampal CA1 neurons isolated from pre-symptomatic 2AQ3 mice exhibit increased persistent sodium current which is likely to underlie hyperexcitability of the hippocampus. During the progression of the seizure disorder there is cell loss and gliosis within the hippocampus in areas CA1, CA3, and the hilus. Four independent transgenic lines expressing the wildtype sodium channel did not exhibit any abnormalities. Conclusions. 2AQ3 mice provide a unique genetic model of limbic seizures, and will be useful for testing pathogenic mechanisms and pharmacological responses of seizures caused by sodium channel dysfunction. The human ortholog, SCN2A, is located on chromosome 2q24 and may contribute to seizure disorders recently mapped to this region. Supported by NIH grants NS34509, NS26729, NS10692, NS01748, NS02081, HD07505; National Multiple Sclerosis grant RG1912, and grants from the Medical Research Service and Rehabilitation Research Service, Veteran's Administration.