SEIZURE SENSITIVITY IN INBRED MOUSE STRAINS: RELATIONSHIP TO KCNJ10 POLYMORPHISM
Abstract number :
3.066
Submission category :
Year :
2002
Submission ID :
1872
Source :
www.aesnet.org
Presentation date :
12/7/2002 12:00:00 AM
Published date :
Dec 1, 2002, 06:00 AM
Authors :
Thomas N. Ferraro, Gregory T. Golden, George G. Smith, James F. Martin, Tracy A. Geringer, Stephanie O. Kratzer, Danielle M. Press, Falk W. Lohoff, Wade H. Berrettini, Russell J. Buono. Psychiatry, University of Pennsylvania, Philadelphia, PA; Research Se
RATIONALE: In order to identify seizure susceptibility genes in mice, we have used a strategy involving quantitative trait locus (QTL) mapping, congenic strain characterization and candidate gene analysis. Previous work from our laboratory documented a locus on distal chromosome 1 that mediates a large part of the dramatic difference in seizure sensitivity between C57BL/6 (B6) (resistant) and DBA/2J (D2) (sensitive) mice. Studies of genes in the critical interval identified a Thr/Ser (B6/D2) polymorphism (C785G) in a potassium ion channel gene (Kcnj10) which makes it a high priority seizure susceptibility candidate. Our objectives were to reduce further the size of the critical interval using B6/D2 congenic strains and to correlate seizure sensitivity with Kcnj10 genotype in other common inbred mouse strains.
METHODS: A series of chromosome 1 interval specific B6.D2 (n = 6) and D2.B6 (n = 3) congenic strains and common inbred strains (n = 15) of mice (n = 10-20/strain) were tested for maximal electroshock seizure threshold (MEST) using a single daily shock with a stepwise (1 mA/day) increment in current until a maximal seizure (tonic hindlimb extension) was elicited. Brain tissue was used for RNA isolation followed by RT-PCR for amplification of Kcnj10. An RFLP assay based on the C785G polymorphism was used to determine Kcnj10 genotype for each strain.
RESULTS: Results showed that all C57-related strains (n = 5) harbor the B6-like (Thr) Kcnj10 polymorphism and this corresponds to a higher MEST. An exception is the C57BLKS strain which exhibits the B6 polymorphism but a D2-like MEST. All other strains (n = 10) exhibit the D2-like (Ser) Kcnj10 polymorphism and tend to have a lower MEST. Reciprocal B6/D2 congenic strains confirm the strong distal chromosome 1 influence on MEST and have allowed systematic reduction of the critical interval to about 3 cM.
CONCLUSIONS: Strain survey results provide evidence for a close correspondence between MEST and a genetic variation in Kcnj10 but as well emphasize the multifactorial nature of seizure sensitivity in common strains of mice. Congenic strain studies document that the critical interval contains Kcnj10 and together with survey results support its continued evaluation as a seizure susceptibility gene.
[Supported by: This work was supported by NIH grants NS33243 and NS40554.]