Mammalian Genome

, Volume 18, Issue 1, pp 23–31

Use of chromosome substitution strains to identify seizure susceptibility loci in mice

  • Melodie R. Winawer
  • Rachel Kuperman
  • Martin Niethammer
  • Steven Sherman
  • Daniel Rabinowitz
  • Irene Plana Guell
  • Christine A. Ponder
  • Abraham A. Palmer
Article

Abstract

Seizure susceptibility varies among inbred mouse strains. Chromosome substitution strains (CSS), in which a single chromosome from one inbred strain (donor) has been transferred onto a second strain (host) by repeated backcrossing, may be used to identify quantitative trait loci (QTLs) that contribute to seizure susceptibility. QTLs for susceptibility to pilocarpine-induced seizures, a model of temporal lobe epilepsy, have not been reported, and CSS have not previously been used to localize seizure susceptibility genes. We report QTLs identified using a B6 (host) × A/J (donor) CSS panel to localize genes involved in susceptibility to pilocarpine-induced seizures. Three hundred fifty-five adult male CSS mice, 58 B6, and 39 A/J were tested for susceptibility to pilocarpine-induced seizures. Highest stage reached and latency to each stage were recorded for all mice. B6 mice were resistant to seizures and slower to reach stages compared to A/J mice. The CSS for Chromosomes 10 and 18 progressed to the most severe stages, diverging dramatically from the B6 phenotype. Latencies to stages were also significantly shorter for CSS10 and CSS18 mice. CSS mapping suggests seizure susceptibility loci on mouse Chromosomes 10 and 18. This approach provides a framework for identifying potentially novel homologous candidate genes for human temporal lobe epilepsy.

References

  1. Baulac S, Huberfeld G, Gourfinkel-An I, Mitropoulou G, Beranger A, et al. (2001) First genetic evidence of GABA(A) receptor dysfunction in epilepsy: a mutation in the gamma2-subunit gene. Nat Genet 28, 46–48PubMedCrossRefGoogle Scholar
  2. Belknap JK (2003) Chromosome substitution strains: some quantitative considerations for genome scans and fine mapping. Mamm Genome 14, 723–732PubMedCrossRefGoogle Scholar
  3. Bergren SK, Chen S, Galecki A, Kearney JA (2005) Genetic modifiers affecting severity of epilepsy caused by mutation of sodium channel Scn2a. Mamm Genome 16, 683–690PubMedCrossRefGoogle Scholar
  4. Borges K, Gearing M, McDermott DL, Smith AB, Almonte AG, et al. (2003) Neuronal and glial pathological changes during epileptogenesis in the mouse pilocarpine model. Exp Neurol 182, 21–34PubMedCrossRefGoogle Scholar
  5. Buck KJ, Finn DA (2001) Genetic factors in addiction: QTL mapping and candidate gene studies implicate GABAergic genes in alcohol and barbiturate withdrawal in mice. Addiction 96, 139–149PubMedCrossRefGoogle Scholar
  6. Buck KJ, Metten P, Belknap JK, Crabbe JC (1997) Quantitative trait loci involved in genetic predisposition to acute alcohol withdrawal in mice. J Neurosci 17, 3946–3955PubMedGoogle Scholar
  7. Buck K, Metten P, Belknap J, Crabbe J (1999) Quantitative trait loci affecting risk for pentobarbital withdrawal map near alcohol withdrawal loci on mouse chromosomes 1, 4, and 11. Mamm Genome 10, 431–437PubMedCrossRefGoogle Scholar
  8. Buono RJ, Lohoff FW, Sander T, Sperling MR, O’Connor MJ, et al. (2004) Association between variation in the human KCNJ10 potassium ion channel gene and seizure susceptibility. Epilepsy Res 58, 175–183PubMedCrossRefGoogle Scholar
  9. Charlier C, Singh NA, Ryan SG, Lewis TB, Reus BE, et al. (1998) A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family [see comments]. Nat Genet 18, 53–55PubMedCrossRefGoogle Scholar
  10. Chen J, Larionov S, Pitsch J, Hoerold N, Ullmann C, et al. (2005) Expression analysis of metabotropic glutamate receptors I and III in mouse strains with different susceptibility to experimental temporal lobe epilepsy. Neurosci Lett 375: 192–197PubMedCrossRefGoogle Scholar
  11. Clement Y, Martin B, Venault P, Chapouthier G (1996) Mouse chromosome 9 involvement in beta-CCM-induced seizures. Neuroreport 7, 2226–2230PubMedGoogle Scholar
  12. Cossette P, Liu L, Brisebois K, Dong H, Lortie A, et al. (2002) Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy. Nat Genet 6, 6Google Scholar
  13. Cowley AW Jr, Roman RJ, Kaldunski ML, Dumas P, Dickhout JG, et al. (2001) Brown Norway chromosome 13 confers protection from high salt to consomic Dahl S rat. Hypertension 37: 456–461PubMedGoogle Scholar
  14. De Fusco M, Becchetti A, Patrignani A, Annesi G, Gambardella A, et al. (2000) The nicotinic receptor beta 2 subunit is mutant in nocturnal frontal lobe epilepsy. Nat Genet 26, 275–276PubMedCrossRefGoogle Scholar
  15. Engel J Jr (2001) A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE Task Force on Classification and Terminology. Epilepsia 42, 796–803PubMedCrossRefGoogle Scholar
  16. Escay A, MacDonald BT, Meisler MH, Baulac S, Huberfeld G, et al. (2000) Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS + 2. Nat Genet 24, 343–345CrossRefGoogle Scholar
  17. Fehr C, Shirley RL, Belknap JK, Crabbe JC,Buck KJ (2002) Congenic mapping of alcohol and pentobarbital withdrawal liability loci to a < 1 centimorgan interval of murine chromosome 4: identification of Mpdz as a candidate gene. J Neurosci 22, 3730–3738PubMedGoogle Scholar
  18. Ferraro TN, Golden GT, Smith GG,Berrettini WH (1995) Differential susceptibility to seizures induced by systemic kainic acid treatment in mature DBA/2J and C57BL/6J mice. Epilepsia 36, 301–307PubMedCrossRefGoogle Scholar
  19. Ferraro TN, Golden GT, Smith GG, Schork NJ, St Jean P, et al. (1997) Mapping murine loci for seizure response to kainic acid. Mamm Genome 8, 200–208PubMedCrossRefGoogle Scholar
  20. Ferraro TN, Golden GT, Snyder R, Laibinis M, Smith GG, et al. (1998) Genetic influences on electrical seizure threshold. Brain Res 813, 207–210PubMedCrossRefGoogle Scholar
  21. Ferraro TN, Golden GT, Smith GG, St Jean P, Schork NJ, et al. (1999) Mapping loci for pentylenetetrazol-induced seizure susceptibility in mice. J Neurosci 19, 6733–6739PubMedGoogle Scholar
  22. Ferraro TN, Golden GT, Smith GG, Longman RL, Snyder RL, et al. (2001) Quantitative genetic study of maximal electroshock seizure threshold in mice: evidence for a major seizure susceptibility locus on distal chromosome 1. Genomics 75, 35–42PubMedCrossRefGoogle Scholar
  23. Ferraro TN, Golden GT, Smith GG, Martin JF, Lohoff FW, et al. (2004) Fine mapping of a seizure susceptibility locus on mouse Chromosome 1: nomination of Kcnj10 as a causative gene. Mamm Genome 15, 239–251PubMedCrossRefGoogle Scholar
  24. Fuerst D, Shah J, Kupsky WJ, Johnson R, Shah A, et al. (2001) Volumetric MRI, pathological, and neuropsychological progression in hippocampal sclerosis. Neurology 57, 184–188PubMedCrossRefGoogle Scholar
  25. Gershenfeld HK, Neumann PE, Li X, St Jean PL, Paul SM (1999) Mapping quantitative trait loci for seizure response to a GABAA receptor inverse agonist in mice. J Neurosci 19, 3731–3738PubMedGoogle Scholar
  26. Hain HS, Crabbe JC, Bergeson SE, Belknap JK (2000) Cocaine-induced seizure thresholds: quantitative trait loci detection and mapping in two populations derived from the C57BL/6 and DBA/2 mouse strains. J Pharmacol Exp Ther 293, 180–187PubMedGoogle Scholar
  27. Harkin LA, Bowser DN, Dibbens LM, Singh R, Phillips F, et al. (2002) Truncation of the GABA(A)-receptor gamma2 subunit in a family with generalized epilepsy with febrile seizures plus. Am J Hum Genet 70, 530–536CrossRefGoogle Scholar
  28. Haug K, Warnstedt M, Alekov AK, Sander T, Ramirez A, et al. (2003) Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies. Nat Genet 33, 527–532PubMedCrossRefGoogle Scholar
  29. Heron SE, Crossland KM, Andermann E, Phillips HA, Hall AJ, et al. (2002) Sodium-channel defects in benign familial nenonatal-infantile seizures. Lancet 360, 851–852PubMedCrossRefGoogle Scholar
  30. Kalachikov S, Evgrafov O, Ross B, Winawer M, Barker-Cummings C, et al. (2002) Mutations in LGI1 cause autosomal-dominant partial epilepsy with auditory features. Nat Genet 30, 335–341PubMedCrossRefGoogle Scholar
  31. Kananura C, Haug K, Sander T, Runge U, Gu W, et al. (2002) A splice-site mutation GABRG2 associated with childhood absence epilsepsy and febrile convulsions. Arch Neurol 59, 1137–1141PubMedCrossRefGoogle Scholar
  32. Leite JP, Garcia-Cairasco N, Cavalheiro EA (2002) New insights from the use of pilocarpine and kainate models. Epilepsy Res 50, 93–103PubMedCrossRefGoogle Scholar
  33. Lenzen KP, Heils A, Lorenz S, Hempelmann A, Hofels S, et al. (2005) Supportive evidence for an allelic association of the human KCNJ10 potassium channel gene with idiopathic generalized epilepsy. Epilepsy Res 63, 113–118PubMedCrossRefGoogle Scholar
  34. Liang M, Yuan B, Rute E, Greene AS, Zou AP, et al. (2002) Renal medullary genes in salt-sensitive hypertension: a chromosomal substitution and cDNA microarray study. Physiol Genomics 8, 139–149PubMedGoogle Scholar
  35. Martin B, Clement Y, Venault P, Chapouthier G (1995) Mouse chromosomes 4 and 13 are involved in beta-carboline-induced seizures. J Hered 86, 274–279PubMedGoogle Scholar
  36. Matin A, Collin GB, Asada Y, Varnum D, Nadeau JH (1999) Susceptibility to testicular germ-cell tumours in a 129.MOLF-Chr 19 chromosome substitution strain. Nat Genet 23, 237–240PubMedCrossRefGoogle Scholar
  37. McKhann GM 2nd, Wenzel HJ, Robbins CA, Sosunov AA, Schwartzkroin PA (2003) Mouse strain differences in kainic acid sensitivity, seizure behavior, mortality, and hippocampal pathology. Neuroscience 122, 551–561PubMedCrossRefGoogle Scholar
  38. Morante-Redolat JM, Gorostidi-Pagola A, Piquer-Sirerol S, Saenz A, Poza JJ, et al. (2002) Mutations in the LGI1/Epitempin gene on 10q24 cause autosomal dominant lateral temporal epilepsy. Hum Mol Genet 11, 1119–1128PubMedCrossRefGoogle Scholar
  39. Nadeau JH, Singer JB, Matin A, Lander ES (2000) Analysing complex genetic traits with chromosome substitution strains. Nat Genet 24, 221–225PubMedCrossRefGoogle Scholar
  40. Neumann PE, Collins RL (1991) Genetic dissection of susceptibility to audiogenic seizures in inbred mice. Proc Natl Acad Sci U S A 88, 5408–5412PubMedCrossRefGoogle Scholar
  41. Neumann PE, Collins RL (1992) Confirmation of the influence of a chromosome 7 locus on susceptibility to audiogenic seizures. Mamm Genome 3, 250–253PubMedCrossRefGoogle Scholar
  42. Noebels JL (2003) The biology of epilepsy genes. Annu Rev Neurosci 26, 599–625PubMedCrossRefGoogle Scholar
  43. Palmer AA, Phillips TJ (2002) Quantitative Trait Locus (QTL) Mapping in Mice. In Methods in Alcohol-Related Neuroscience Research, Liu Y, Lovinger DM, eds. (Boca Raton, FL: CRC Press), pp 1–30Google Scholar
  44. Phillips TJ, Belknap JK, Hitzemann RJ, Buck KJ, Cunningham CL, et al. (2002) Harnessing the mouse to unravel the genetics of human disease. Genes Brain Behav 1, 14–26PubMedCrossRefGoogle Scholar
  45. Pitkanen A, Sutula TP (2002) Is epilepsy a progressive disorder? Prospects for new therapeutic approaches in temporal-lobe epilepsy. Lancet Neurol 1, 173–181PubMedCrossRefGoogle Scholar
  46. Racine RJ (1972) Modification of seizure activity by eletrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol 32, 281–294PubMedCrossRefGoogle Scholar
  47. Schauwecker PE (2002) Modulation of cell death by mouse genotype: differential vulnerability to excitatory amino acid-induced lesions. Exp Neurol 178, 219–235PubMedCrossRefGoogle Scholar
  48. Schauwecker PE, Steward O (1997) Genetic determinants of susceptibility to excitotoxic cell death: implications for gene targeting approaches. Proc Natl Acad Sci U S A 94, 4103–4108PubMedCrossRefGoogle Scholar
  49. Schauwecker PE, Williams RW, Santos JB (2004) Genetic control of sensitivity to hippocampal cell death induced by kainic acid: a quantitative trait loci analysis. J Comp Neurol 477, 96–107PubMedCrossRefGoogle Scholar
  50. Semah F, Picot MC, Adam C, Broglin D, Arzimanoglou A, et al. (1998) Is the underlying cause of epilepsy a major prognostic factor for recurrence? Neurology 51, 1256–1262PubMedGoogle Scholar
  51. Shorvon SD (2002) Does convulsive status epilepticus (SE) result in cerebral damage or affect the course of epilepsy–the epidemiological and clinical evidence? Prog Brain Res 135, 85–93PubMedCrossRefGoogle Scholar
  52. Singer JB, Hill AE, Burrage LC, Olszens KR, Song J, et al. (2004) Genetic dissection of complex traits with chromosome substitution strains of mice. Science 304, 445–448PubMedCrossRefGoogle Scholar
  53. Singh NA, Charlier C, Stauffer D, Dupont BR, Leach RJ, et al. (1998) A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns [see comments]. Nat Genet 18, 25–29PubMedCrossRefGoogle Scholar
  54. Steinlein OK, Mulley JC, Propping P, Wallace RH, Phillips HA, et al. (1995) A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet 11, 201–203PubMedCrossRefGoogle Scholar
  55. Stekiel TA, Contney SJ, Bosnjak ZJ, Kampine JP, Roman RJ, et al. (2006) Chromosomal substitution-dependent differences in cardiovascular responses to sodium pentobarbital. Anesth Analg 102, 799–805PubMedCrossRefGoogle Scholar
  56. Stephen LJ, Kwan P, Brodie MJ (2001) Does the cause of localistion-related epilepsy influence the response to antiepileptic drug treatment? Epilepsia 42, 357–362PubMedCrossRefGoogle Scholar
  57. Sugawara T, Mazaki-Miyazaki E, Ito M, Nagafuji H, Fukuma G, et al. (2001a) Nav1.1 mutations cause febrile seizures associated with afebrile partial seizures. Neurology 57, 703–705Google Scholar
  58. Sugawara T, Tsurubuchi Y, Agarwala KL, Ito M, Fukuma G, et al. (2001b) A missense mutation of the Na + channel alpha II subunit gene Na(v)1.2 in a patient with febrile and afebrile seizures causes channel dysfunction. Proc Natl Acad Sci U S A 98, 6384–6389CrossRefGoogle Scholar
  59. Sutula TP, Pitkanen A (2001) More evidence for seizure-induced neuron loss: is hippocampal sclerosis both cause and effect of epilepsy? Neurology 57, 169–170PubMedCrossRefGoogle Scholar
  60. Suzuki T, Delgado-Escueta AV, Aguan K, Alonso ME, Shi J, et al. (2004) Mutations in EFHC1 cause juvenile myoclonic epilepsy. Nat Genet 36, 842–849PubMedCrossRefGoogle Scholar
  61. Turski L, Ikonomidou C, Turski WA, Bortolotto ZA,Cavalheiro EA (1989) Review: cholinergic mechanisms and epileptogenesis. The seizures induced by pilocarpine: a novel experimental model of intractable epilepsy. Synapse 3, 154–171PubMedCrossRefGoogle Scholar
  62. Turski WA (2000) Pilocarpine-induced seizures in rodents—17 years on Pol. J Pharmacol 52, 63–65Google Scholar
  63. Wallace RH, Wang DW, Singh R, Scheffer IE, George AL Jr, et al. (1998) Febrile seizures and generalized epilepsy associated with a mutation in the Na + -channel beta1 subunit gene SCN1B. Nat Genet 19, 366–370PubMedCrossRefGoogle Scholar
  64. Wallace RH, Marini C, Petrou S, Harkin LA, Bowser DN, et al. (2001a) Mutant GABA(A) receptor gamma2-subunit in childhood absence epilepsy and febrile seizures. Nat Genet 28, 49–52CrossRefGoogle Scholar
  65. Wallace RH, Scheffer IE, Barnett S, Richards M, Dibbens L, et al. (2001b) Neuronal sodium-channel alpha1-subunit mutations in generalized epilepsy with febrile seizures plus. Am J Hum Genet 68, 859–865CrossRefGoogle Scholar
  66. Wallace RH, Hodgson BL, Grinton BE, Gardiner RM, Robinson R, et al. (2003) Sodium channel alpha1-subunit mutations in severe myoclonic epilepsy of infancy and infantile spasms. Neurology 61, 765–769PubMedGoogle Scholar
  67. Youngren KK, Nadeau JH, Matin A (2003) Testicular cancer susceptibility in the 129.MOLF-Chr19 mouse strain: additive effects, gene interactions and epigenetic modifications. Hum Mol Genet 12, 389–398PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2007

Authors and Affiliations

  • Melodie R. Winawer
    • 1
  • Rachel Kuperman
    • 2
  • Martin Niethammer
    • 1
  • Steven Sherman
    • 3
  • Daniel Rabinowitz
    • 4
  • Irene Plana Guell
    • 4
  • Christine A. Ponder
    • 5
  • Abraham A. Palmer
    • 6
  1. 1.Department of NeurologyColumbia UniversityNew YorkUSA
  2. 2.Department of Pediatric NeurologyColumbia UniversityNew YorkUSA
  3. 3.Department of EpidemiologyMailman School of Public Health, Columbia UniversityNew YorkUSA
  4. 4.Department of StatisticsColumbia UniversityNew YorkUSA
  5. 5.Department of Genetics and DevelopmentColumbia UniversityNew YorkUSA
  6. 6.Department of Human GeneticsUniversity of ChicagoChicagoUSA
  7. 7.Department of NeurologyColumbia University, GH Sergievsky CenterNew YorkUSA

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