Skip to main content
SpringerLink
Log in

Mapping murine loci for seizure response to kainic acid

  • Original Contribution
  • Published:
Mammalian Genome Aims and scope Submit manuscript

Abstract

Mature DBA/2J (D2) mice are very sensitive to seizures induced by various chemical and physical stimuli, whereas C57BL/6J (B6) mice are relatively seizure resistant. We have conducted a genome-wide search for quantitative trait loci (QTLs) influencing the differential sensitivity of these strains to kainic acid (KA)-induced seizures by studying an F2 intercross population. Parental, F1, and F2 mice (8–10 weeks of age) were injected subcutaneously with 25 mg/kg of KA and observed for 3 h. Latencies to focal and generalized seizures and status epilepticus were recorded and used to calculate an overall seizure score. Results of seizure testing indicated that the difference in susceptibility to KA-induced seizures between D2 and B6 mice is a polygenic phenomenon with at least 65% of the variance due to genetic factors. First-pass genome screening (10-cM marker intervals) in F2 progeny (n = 257) documented a QTL of moderate effect on Chromosome (Chr) 1 with a peak LOD score of 5.5 (17% of genetic variance explained) localized between D1Mit30 and D1Mit16. Provisional QTLs of small effect were detected on Chr 11 (D11Mit224–D11Mitl4), 15 (D15Mit6–D15Mit46) and 18 (D18Mit9–D18Mitl44). Multiple locus models generally confirmed the Mapmaker/QTL results and also provided evidence for another QTL on Chr 4 (D4Mit9). Multilocus analysis of seizure severity suggested that additional loci on Chrs 5 (D5Mit11), 7 (D7Mit66), and 15 (D15Nds2) might also contribute to KA-induced seizure response. Overall, our results document a complex genetic determinism for KA-induced seizures in these mouse strains with contributions from as many as eight QTLs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Anderson WR, Franck JE, Stahl WL, Maki AA (1994). Na, K-ATPase is decreased in hippocampus of kainate-lesioned rats. Epilepsy Res 17, 221–231

    Article  PubMed  CAS  Google Scholar 

  • Bagetta G, Iannone M, Palma E, Rodino P, Granato T, and Nistico G. (1995) Lack of involvement of nitric oxide in the mechanisms of seizures and hippocampal damage produced by kainate and oubain in rats. Neurodegeneration 4, 43–49

    Article  PubMed  CAS  Google Scholar 

  • Ben-Ari Y (1985). Limbic seizure and brain damage produced by kainic acid: mechanisms and relevance to human temporal lobe epilepsy. Neuroscience 14, 375–403

    Article  PubMed  CAS  Google Scholar 

  • Ben-Ari Y, Tremblay E, Riche D, Ghilini G, Naquet R (1981). Electrographic, clinical and pathological alterations following systemic administration of kainic acid, bicuculline and penetrazole: metabolic mapping using the deoxyglucose method with special reference to the pathology of epilepsy. Neuroscience 6, 1361–1391

    Article  PubMed  CAS  Google Scholar 

  • Berrettini WB, Ferraro TN, Alexander R, Vogel WV (1994). Quantitative trait loci mapping of three loci controlling morphine preference using inbred mouse strains. Nature Genet 7, 54–58

    Article  PubMed  CAS  Google Scholar 

  • Brines ML, Dare AO, deLanerolle NC (1995). The cardiac glycoside oubain potentiates excitotoxic injury of adult neurons in rat hippocampus. Neurosci Lett 191, 145–148

    Article  PubMed  CAS  Google Scholar 

  • Collingridge GL, Lester RAJ (1989). Excitatory amino acid receptors in the vertebrate central nervous system. Pharmacol. Rev. 40, 143–210

    Google Scholar 

  • Curtis D (1996). Genetic dissection of complex traits (in reply to correspondence). Nature Genet 11, 355–358

    Google Scholar 

  • DeBry RW, Seidin MF (1996). Human/mouse homology relationships. Genomics 33, 337–351

    Article  PubMed  CAS  Google Scholar 

  • Delgado-Escueta AV, Greenberg D, Weissbecker K, Liu A, Treiman L, Sparkes R, Park MS, Barbetti A, Terasaki PI (1990). Gene mapping in the idiopathic generalized epilepsies: juvenile myoclonic epilepsy, childhood absence epilepsy, epilepsy with grand mal seizures, and early childhood myoclonic epilepsy. Epilepsia 31 (Suppl. 3), S19-S29

    Article  PubMed  Google Scholar 

  • Dietrich WF, Miller JC, Steen RG, Merchant M, Damron D, Nahf R, Gross A, Joyce DC, Wessel M, Dredge RD, Marquis A, Stein LD, Goodman N, Page, DC, Lander ES (1994). A genetic map of the mouse with 4,006 simple sequence length polymorphisms. Nature Genet 7, 220–245

    Article  PubMed  CAS  Google Scholar 

  • Dietrich WF, Miller JC, Steen RG, Merchant M, Damron-Boles D, Husain Z, Dredge R, Daly M, Ingalls K, O’Connor T, Evans C, DeAngelis M, Levinson D, Kruglyak L, Goodman N, Copeland N, Jenkins N, Hawkins T, Lincoln S, Page D, Lander E. (1996) A comprehensive genetic map of the mouse genome. Nature 380, 149–152

    Article  PubMed  CAS  Google Scholar 

  • Engstrom FL, Woodbury DM (1988). Seizure susceptibility in DBA and C57 mice: the effects of various convulsants. Epilepsia 29, 389–395

    Article  PubMed  CAS  Google Scholar 

  • Ferraro TN, Golden GT, Smith GG, Berrettini WH (1995). Differential susceptibility to seizures induced by kainic acid. Epilepsia 36, 301–307

    Article  PubMed  CAS  Google Scholar 

  • Frankel WN, Taylor BA, Noebels JL, Lutz CM (1994). Genetics epilepsy model derived from common inbred mouse strains. Genetics 138, 1–9

    Google Scholar 

  • Frankel WN, Valenzuela A, Lutz CM, Johnson EW, Dietrich WF, JM Coffin (1995). New seizure frequency QTL and the complex genetics of epilepsy in EL mice. Mamm Genome 6, 830–838

    Article  PubMed  CAS  Google Scholar 

  • Johnson SW, Seutin V, North RA (1992). Burst firing in dopamine neurons induced by N-methyl-D-aspartate: role of electrogenic sodium pump. Science 258, 665–667

    Article  PubMed  CAS  Google Scholar 

  • Kent RB, Fallows DA, Geissler E, Glaser T, Rettig Emanuel J, Lalley PA, Levenson R, Houseman DE (1987). Genes encoding a and B subunits of Na, K-ATPase are located on three different chromosomes in the mouse. Proc Natl Acad Sci USA 84, 5369–5373

    Article  PubMed  CAS  Google Scholar 

  • Kosobud AE, Crabbe JC (1990). Genetic correlations among inbred strain sensitivities to convulsions induced by 9 convulsant drugs. Brain Res 526, 8–16

    Article  PubMed  CAS  Google Scholar 

  • Kruglyak L, Lander ES (1995). A nonparametric approach for mapping quantitative trait loci. Genetics 139, 1421–1428

    PubMed  CAS  Google Scholar 

  • Lahiri DK, Nurnberger JI (1991). A rapid non-enzymatic method for the preparation of high molecular weight DNA from blood for RFLP studies. Nucleic Acids Res 19, 5444

    Article  PubMed  CAS  Google Scholar 

  • Lander ES, Botstein D (1989). Mapping Mendelian factors underlying quantitative traits using RFLP linkage maps. Genetics 121, 185–199

    PubMed  CAS  Google Scholar 

  • Lander ES, Kruglyak L (1995). Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nature Genet 11, 241–247

    Article  PubMed  CAS  Google Scholar 

  • Lander ES, Kruglyak L (1996). Genetic dissection of complex traits (in reply to correspondence). Nature Genet 11, 355–358

    Google Scholar 

  • Lander ES, Green P, Abrahamson J, Barlow A, Daly MJ, Lincoln SE, Newburg L (1987). MAPMAKER: An interactive computer package for constructing primary genetic linkage maps of experimental and natural populations. Genomics 1, 174–181

    Article  PubMed  CAS  Google Scholar 

  • Martin B, Marchaland C, Chapouthier G, Motta R (1994). Evidence for a multigenic system controlling methyl-B-carboline-S-carboxylate (B-CCM)-induced seizures. Behav Genet 24, 285–297

    Article  PubMed  CAS  Google Scholar 

  • Martin B, Clement Y, Venault P, Chapouthier G (1995). Mouse chromosomes 4 and 13 are involved in B-carboline-induced seizures. J Hered 86, 274–279

    PubMed  CAS  Google Scholar 

  • McAleer MA, Reifsnyder P, Palmer SM, Prochazka M, Love JM, Copeman JB, Powell EE, Rodrigues NR, Prins JB, Serreze DV, DeLarato NH, Wicker LS, Peterson LB, Schork NJ, Todd JA, Leiter EH (1995). Crosses of NOD mice with the related NON strain. Diabetes 44, 1186–1195

    Article  PubMed  CAS  Google Scholar 

  • Nadler JV (1981). Kainic acid as a tool for the study of temporal lobe epilepsy. Life Sci 29, 2031–2042

    Article  PubMed  CAS  Google Scholar 

  • Neumann PE, Collins RL (1991). Genetic dissection of susceptibility to audiogenic seizures in inbred mice. Proc Natl Acad Sci USA 88, 5408–5412

    Article  PubMed  CAS  Google Scholar 

  • Neumann PE, Seyfried TN (1990). Mapping of two genes that influence susceptibility to audiogenic seizures in crosses of C57BL/6J and DBA/ 2J mice. Behav Genet 20, 307–323

    Article  PubMed  CAS  Google Scholar 

  • Risch N, Ghosh S, Todd JA (1993). Statistical evaluation of multiple-locus linkage data in experimental species and its relevance to human studies: application to nonobese diabetic (NOD) mouse and human insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 53, 702–714

    PubMed  CAS  Google Scholar 

  • Rise ML, Frankel WN, Coffin JM, Seyfried TN (1991). Genes for epilepsy mapped in the mouse. Science 253, 669–673

    Article  PubMed  CAS  Google Scholar 

  • Schork NJ, Krieger JE, Trolliet MR, Franchini KG, Koike G, Krieger EM, Lander ES, Dzau VJ, Jacob HJ (1995). A biometrical genome search in rats reveals the multigenic basis of blood pressure variation. Genome Res 5, 164–172

    Article  PubMed  CAS  Google Scholar 

  • Taylor BA and Phillips SJ (1996) Detection of obesity QTLs on mouse chromosome 1 and 7 by selective DNA pooling. Genomics 34, 389–398

    Article  PubMed  CAS  Google Scholar 

  • Tecott LH, Sun LM, Akara SF, Strack AM, Lowenstein DH, Dallman MF, Julius D (1995) Eating disorder and epilepsy in mice lacking 5-Ht2c serotonin receptors. Nature 374, 542–546

    Article  PubMed  CAS  Google Scholar 

  • Warden CH, Fisher JS, Shoemaker SM, Wen P-Z, Svenson KL (1995) Identification of four chromosomal loci determining obesity in a multi-factorial mouse model. J. Clin Invest 95, 1545–1552

    Article  PubMed  CAS  Google Scholar 

  • Weissbecker KA, Durner M, Janz D, Scaramelli A, Sparkes RS, Spence MA (1991). Confirmation of linkage between juvenile myoclonic epilepsy locus and the HLA region of chromosome 6. Am J Med Genet 38, 32–36

    Article  PubMed  CAS  Google Scholar 

  • West DB, Waguespack J, York B, Goudey-Lefevre J, Price RA (1994) Genetics of dietary obesity in AKR/J × SWR/J mice: segregation of the trait and identification of a linked locus on chromosome 4. Mamm Genome 5, 546–552

    Article  PubMed  CAS  Google Scholar 

  • Whitehouse WP, Rees M, Curtis D, Sundqvist A, Parker K, Chung E, Baralle D, Gardiner RM (1993). Linkage analysis of idiopathic generalized epilepsy (IGE) and marker loci on chromosome 6p in families of patients with juvenile myoclonic epilepsy: no evidence for an epilepsy locus in the HLA region. Am J Hum Genet 53, 652–662

    PubMed  CAS  Google Scholar 

  • Witte JS, Elston RC, Schork NJ (1996). Genetic dissection of complex traits. Nature Genet 11, 355–358

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Psychiatry, Thomas Jefferson University, 19107, Philadelphia, Pennsylvania, USA

    T. N. Ferraro, H. Choi & W. H. Berrettini

  2. Department of Pharmacology, Thomas Jefferson University, 19107, Philadelphia, Pennsylvania, USA

    T. N. Ferraro, C. Ballas & W. H. Berrettini

  3. Department of Neurology, Thomas Jefferson University, 19107, Philadelphia, Pennsylvania, USA

    G. T. Golden

  4. Department of Veterans Affairs Medical Center, Research Service, 19320, Coatesville, Pennsylvania, USA

    G. T. Golden & G. G. Smith

  5. Departments of Epidemiology and Biostatistics, Case Western Reserve University, 44106, Cleveland, Ohio, USA

    N. J. Schork & P. St. Jean

  6. Department of Genetics, Case Western Reserve University, 44106, Cleveland, Ohio, USA

    N. J. Schork

  7. Department of Biostatistics, Harvard University, Boston, Massachusetts, USA

    N. J. Schork

  8. The Jackson Laboratory, 04609, Bar Harbor, Maine, USA

    N. J. Schork

Authors
  1. T. N. Ferraro
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G. T. Golden
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G. G. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. N. J. Schork
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P. St. Jean
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C. Ballas
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. H. Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. W. H. Berrettini
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ferraro, T.N., Golden, G.T., Smith, G.G. et al. Mapping murine loci for seizure response to kainic acid. Mammalian Genome 8, 200–208 (1997). https://doi.org/10.1007/s003359900389

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s003359900389

Keywords

Search

Navigation