International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

B7. Transgenic Expression of a Mutation in the Sodium Channel Gene Scn2a Results in Seizures and Behavioral Abnormalities

Kearney, J. A.1, Plummer, N. W1, Marianne R. Smith2, Jaideep Kapur3, Theodore R. Cummins4, Stephen G. Waxman4, Alan L. Goldin2 and Miriam H. Meisler1
1Dept. Human Genetics, U. Michigan Ann Arbor,
Dept. Microbiology and Immunology, U. California Irvine,
Dept. Neurology, U. Virginia Richmond and
Dept. Neurology, Yale University.

Mutations that delay the inactivation of sodium channels in muscle are responsible for inherited episodic paralysis, but this type of mutation has not previously been described in a neuronal sodium channel. The neuronal sodium channel Scn2a is located in the proximal region of mouse chromosome 2. We studied a mutation in a cytoplasmic S4-S5 linker of the sodium channel gene Scn2a which results in slowed inactivation and increased persistent current when expressed in Xenopus oocytes. The neuron-specific enolase (NSE) promoter was used to direct in vivo expression of the mutated channel in transgenic mice. Three transgenic lines exhibited seizures, and line Q54 was characterized in detail. The seizures in these mice begin at two months of age and are accompanied by behavioral arrest and stereotyped repetitive behaviors. Continuous EEG monitoring detected focal seizure activity in the hippocampus, which in some instances generalizes to involve the cortex. Hippocampal CA1 neurons isolated from presymptomatic Q54 mice exhibit increased persistent sodium current which may underlie hyperexcitability in the hippocampus. During the progression of the disorder there is extensive cell loss and gliosis within the hippocampus in areas CA1, CA2, CA3 and the hilus. The lifespan of Q54 mice is shortened and only 25% of the mice survive beyond 6 months of age. Four independent transgenic lines expressing the wildtype sodium channel were examined and did not exhibit any abnormalities. Q54 mice provide a genetic model that will be useful for testing the effect of pharmacological intervention on progression of seizures caused by sodium channel dysfunction. The unusual repetitive behaviors exhibited by these mice also resemble some types of complex human psychiatric disorders. The human ortholog, SCN2A, is located on chromosome 2q22-24 and is a candidate gene for related human disorders.

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