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Link Between Absence Seizures and T-Type Calcium Channels

  • Yucai Chen
  • W. Davis Parker
Chapter

Abstract

An animal model of human absence epilepsy containing a G to C mutation of the Cav3.2 T-type Ca2+ channel gene (Cacna1h) ties together the gene mutation, increased T-type Ca2+ channel activity and the epileptic phenotype. Mice lacking a related gene (Cacna1a) also show enhanced T-type Ca2+ current and increased susceptibility to absence seizures. On the other hand, mutations that decrease T-type Ca2+ channel activity in thalamocortical relay neurons display no spike–wave discharges associated with absence seizures. These animal models are supported by genetic studies showing defects in T-type Ca2+ channel function in humans suffering from epilepsy. Thus, in both human and animal studies, T-type Ca2+ channel antagonists show promise in the treatment of absence seizures.

Keywords

Absence Seizure Absence Epilepsy Wave Discharge Juvenile Myoclonic Epilepsy Burst Firing 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

We thank Peggy Mankin and Hongyi Chen for manuscript preparation. This work was funded by the Pediatrics Department fund, Children’s Hospital of Illinois.

References

  1. Astori S, Wimmer RD, Prosser HM, Corti C, Corsi M, Liaudet N, Volterra A, Franken P, Adelman JP, Luthi A (2011) The Ca(V)3.3 calcium channel is the major sleep spindle pacemaker in thalamus. Proc Natl Acad Sci USA 108:13823–13828PubMedCentralPubMedCrossRefGoogle Scholar
  2. Barton ME, Eberle EL, Shannon HE (2005) The antihyperalgesic effects of the T-type calcium channel blockers ethosuximide, trimethadione, and mibefradil. Eur J Pharmacol 521:79–85PubMedCrossRefGoogle Scholar
  3. Becker AJ, Pitsch J, Sochivko D, Opitz T, Staniek M, Chen CC, Campbell KP, Schoch S, Yaari Y, Beck H (2008) Transcriptional upregulation of Cav3.2 mediates epileptogenesis in the pilocarpine model of epilepsy. J Neurosci 28:13341–13353PubMedCrossRefGoogle Scholar
  4. Broicher T, Seidenbecher T, Meuth P, Munsch T, Meuth SG, Kanyshkova T, Pape HC, Budde T (2007) T-current related effects of antiepileptic drugs and a Ca2+ channel antagonist on thalamic relay and local circuit interneurons in a rat model of absence epilepsy. Neuropharmacology 53:431–446PubMedCrossRefGoogle Scholar
  5. Burgess DL, Noebels JL (1999a) Single gene defects in mice: the role of voltage-dependent calcium channels in absence models. Epilepsy Res 36:111–122PubMedCrossRefGoogle Scholar
  6. Burgess DL, Noebels JL (1999b) Voltage-dependent calcium channel mutations in neurological disease. Ann N Y Acad Sci 868:199–212PubMedCrossRefGoogle Scholar
  7. Cain SM, Snutch TP (2010) Contributions of T-type calcium channel isoforms to neuronal firing. Channels 4:475–482PubMedCentralPubMedCrossRefGoogle Scholar
  8. Cain SM, Snutch TP (2013) T-type calcium channels in burst-firing, network synchrony, and epilepsy. Biochim Biophys Acta 1828:1572–1578PubMedCrossRefGoogle Scholar
  9. Chang BS, Lowenstein DH (2003) Epilepsy. N Engl J Med 349:1257–1266PubMedCrossRefGoogle Scholar
  10. Chen Y, Lu J, Pan H, Zhang Y, Wu H, Xu K, Liu X, Jiang Y, Bao X, Yao Z, Ding K, Lo WH, Qiang B, Chan P, Shen Y, Wu X (2003a) Association between genetic variation of CACNA1H and childhood absence epilepsy. Ann Neurol 54:239–243PubMedCrossRefGoogle Scholar
  11. Chen Y, Lu J, Zhang Y, Pan H, Wu H, Xu K, Liu X, Jiang Y, Bao X, Zhou J, Liu W, Shi G, Shen Y, Wu X (2003b) T-type calcium channel gene alpha (1G) is not associated with childhood absence epilepsy in the Chinese Han population. Neurosci Lett 341:29–32PubMedCrossRefGoogle Scholar
  12. Cribbs LL, Lee JH, Yang J, Satin J, Zhang Y, Daud A, Barclay J, Williamson MP, Fox M, Rees M, Perez-Reyes E (1998) Cloning and characterization of alpha1H from human heart, a member of the T-type Ca2+ channel gene family. Circ Res 83:103–109PubMedCrossRefGoogle Scholar
  13. Crunelli V, Leresche N (2002) Childhood absence epilepsy: genes, channels, neurons and networks. Nat Rev Neurosci 3:371–382PubMedCrossRefGoogle Scholar
  14. Erisir A, Van Horn SC, Bickford ME, Sherman SM (1997a) Immunocytochemistry and distribution of parabrachial terminals in the lateral geniculate nucleus of the cat: a comparison with corticogeniculate terminals. J Comp Neurol 377:535–549PubMedCrossRefGoogle Scholar
  15. Erisir A, Van Horn SC, Sherman SM (1997b) Relative numbers of cortical and brainstem inputs to the lateral geniculate nucleus. Proc Natl Acad Sci USA 94:1517–1520PubMedCentralPubMedCrossRefGoogle Scholar
  16. Ernst WL, Zhang Y, Yoo JW, Ernst SJ, Noebels JL (2009) Genetic enhancement of thalamocortical network activity by elevating alpha 1G-mediated low-voltage-activated calcium current induces pure absence epilepsy. J Neurosci 29:1615–1625PubMedCentralPubMedCrossRefGoogle Scholar
  17. Fisher RS, van Emde BW, Blume W, Elger C, Genton P, Lee P, Engel J Jr (2005) Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia 46:470–472PubMedCrossRefGoogle Scholar
  18. Fletcher CF, Frankel WN (1999) Ataxic mouse mutants and molecular mechanisms of absence epilepsy. Hum Mol Genet 8:1907–1912PubMedCrossRefGoogle Scholar
  19. Fletcher CF, Lutz CM, O’Sullivan TN, Shaughnessy JD Jr, Hawkes R, Frankel WN, Copeland NG, Jenkins NA (1996) Absence epilepsy in tottering mutant mice is associated with calcium channel defects. Cell 87:607–617PubMedCrossRefGoogle Scholar
  20. Fuentealba P, Steriade M (2005) The reticular nucleus revisited: intrinsic and network properties of a thalamic pacemaker. Prog Neurobiol 75:125–141PubMedCrossRefGoogle Scholar
  21. Futatsugi Y, Riviello JJ Jr (1998) Mechanisms of generalized absence epilepsy. Brain Dev 20:75–79PubMedCrossRefGoogle Scholar
  22. Heron SE, Khosravani H, Varela D, Bladen C, Williams TC, Newman MR, Scheffer IE, Berkovic SF, Mulley JC, Zamponi GW (2007) Extended spectrum of idiopathic generalized epilepsies associated with CACNA1H functional variants. Ann Neurol 62:560–568PubMedCrossRefGoogle Scholar
  23. Joksovic PM, Nelson MT, Jevtovic-Todorovic V, Patel MK, Perez-Reyes E, Campbell KP, Chen CC, Todorovic SM (2006) Cav3.2 is the major molecular substrate for redox regulation of T-type Ca2+ channels in the rat and mouse thalamus. J Physiol 574:415–430PubMedCentralPubMedCrossRefGoogle Scholar
  24. Khosravani H, Zamponi GW (2006) Voltage-gated calcium channels and idiopathic generalized epilepsies. Physiol Rev 86:941–966PubMedCrossRefGoogle Scholar
  25. Khosravani H, Altier C, Simms B, Hamming KS, Snutch TP, Mezeyova J, McRory JE, Zamponi GW (2004) Gating effects of mutations in the Cav3.2 T-type calcium channel associated with childhood absence epilepsy. J Biol Chem 279:9681–9684PubMedCrossRefGoogle Scholar
  26. Khosravani H, Bladen C, Parker DB, Snutch TP, McRory JE, Zamponi GW (2005) Effects of Cav3.2 channel mutations linked to idiopathic generalized epilepsy. Ann Neurol 57:745–749PubMedCrossRefGoogle Scholar
  27. Kim D, Song I, Keum S, Lee T, Jeong MJ, Kim SS, McEnery MW, Shin HS (2001) Lack of the burst firing of thalamocortical relay neurons and resistance to absence seizures in mice lacking alpha(1G) T-type Calcium channels. Neuron 31:35–45PubMedCrossRefGoogle Scholar
  28. Kostopoulos GK (2001) Involvement of the thalamocortical system in epileptic loss of consciousness. Epilepsia 42(Suppl 3):13–19PubMedCrossRefGoogle Scholar
  29. Lee JH, Daud AN, Cribbs LL, Lacerda AE, Pereverzev A, Klockner U, Schneider T, Perez-Reyes E (1999) Cloning and expression of a novel member of the low voltage-activated T-type calcium channel family. J Neurosci 19:1912–1921PubMedGoogle Scholar
  30. Leresche N, Parri HR, Erdemli G, Guyon A, Turner JP, Williams SR, Asprodini E, Crunelli V (1998) On the action of the anti-absence drug ethosuximide in the rat and cat thalamus. J Neurosci 18:4842–4853PubMedGoogle Scholar
  31. Liao YF, Tsai ML, Chen CC, Yen CT (2011) Involvement of the Cav3.2 T-type calcium channel in thalamic neuron discharge patterns. Mol Pain 7:43PubMedCentralPubMedCrossRefGoogle Scholar
  32. Liu XB, Honda CN, Jones EG (1995) Distribution of four types of synapse on physiologically identified relay neurons in the ventral posterior thalamic nucleus of the cat. J Comp Neurol 352:69–91PubMedCrossRefGoogle Scholar
  33. Lowenstein D, Messing R (2007) Epilepsy genetics: yet more exciting news. Ann Neurol 62:549–550PubMedCrossRefGoogle Scholar
  34. Lu Y, Wang X (2009) Genes associated with idiopathic epilepsies: a current overview. Neurol Res 31:135–143PubMedCrossRefGoogle Scholar
  35. Lu JJ, Zhang YH, Chen YC, Pan H, Wang JL, Zhang L, Wu HS, Xu KM, Liu XY, Tao LD, Shen Y, Wu XR (2005) T-type calcium channel gene-CACNA1H is a susceptibility gene to childhood absence epilepsy. Zhonghua Er Ke Za Zhi 43:133–136PubMedGoogle Scholar
  36. Marescaux C, Vergnes M (1995) Genetic absence epilepsy in rats from Strasbourg (GAERS). Ital J Neurol Sci 16:113–118PubMedCrossRefGoogle Scholar
  37. McCormick DA, Bal T (1997) Sleep and arousal: thalamocortical mechanisms. Annu Rev Neurosci 20:185–215PubMedCrossRefGoogle Scholar
  38. Mulley JC, Scheffer IE, Harkin LA, Berkovic SF, Dibbens LM (2005) Susceptibility genes for complex epilepsy. Hum Mol Genet 14:R243–R249PubMedCrossRefGoogle Scholar
  39. Panayiotopoulos CP, Obeid T, Waheed G (1989) Differentiation of typical absence seizures in epileptic syndromes. A video EEG study of 224 seizures in 20 patients. Brain 112:1039–1056PubMedCrossRefGoogle Scholar
  40. Peloquin JB, Khosravani H, Barr W, Bladen C, Evans R, Mezeyova J, Parker D, Snutch TP, McRory JE, Zamponi GW (2006) Functional analysis of Ca3.2 T-type calcium channel mutations linked to childhood absence epilepsy. Epilepsia 47:655–658PubMedCrossRefGoogle Scholar
  41. Perez-Reyes E (2003) Molecular physiology of low-voltage-activated T-type calcium channels. Physiol Rev 83:117–161PubMedGoogle Scholar
  42. Perez-Reyes E, Cribbs LL, Daud A, Lacerda AE, Barclay J, Williamson MP, Fox M, Rees M, Lee JH (1998) Molecular characterization of a neuronal low-voltage-activated T-type calcium channel. Nature 391:896–900PubMedCrossRefGoogle Scholar
  43. Perez-Reyes E, Lee JH, Cribbs LL (1999) Molecular characterization of two members of the T-type calcium channel family. Ann N Y Acad Sci 868:131–143PubMedCrossRefGoogle Scholar
  44. Pinault D, O’Brien TJ (2005) Cellular and network mechanisms of genetically-determined absence seizures. Thalamus Relat Syst 3:181–203PubMedCentralPubMedCrossRefGoogle Scholar
  45. Porter RJ (1993) The absence epilepsies. Epilepsia 34(Suppl 3):S42–S48PubMedGoogle Scholar
  46. Powell KL, Cain SM, Ng C, Sirdesai S, David LS, Kyi M, Garcia E, Tyson JR, Reid CA, Bahlo M, Foote SJ, Snutch TP, O'Brien TJ (2009) A Cav3.2 T-type calcium channel point mutation has splice-variant-specific effects on function and segregates with seizure expression in a polygenic rat model of absence epilepsy. J Neurosci 29:371–380PubMedCrossRefGoogle Scholar
  47. Rajakulendran S, Graves TD, Labrum RW, Kotzadimitriou D, Eunson L, Davis MB, Davies R, Wood NW, Kullmann DM, Hanna MG, Schorge S (2010) Genetic and functional characterisation of the P/Q calcium channel in episodic ataxia with epilepsy. J Physiol 588:1905–1913PubMedCentralPubMedCrossRefGoogle Scholar
  48. Rajakulendran S, Kaski D, Hanna MG (2012) Neuronal P/Q-type calcium channel dysfunction in inherited disorders of the CNS. Nat Rev Neurol 8:86–96PubMedCrossRefGoogle Scholar
  49. Ramcharan EJ, Gnadt JW, Sherman SM (2000) Burst and tonic firing in thalamic cells of unanesthetized, behaving monkeys. Vis Neurosci 17:55–62PubMedCrossRefGoogle Scholar
  50. Sherman SM (2001) Tonic and burst firing: dual modes of thalamocortical relay. Trends Neurosci 24:122–126PubMedCrossRefGoogle Scholar
  51. Singh B, Monteil A, Bidaud I, Sugimoto Y, Suzuki T, Hamano S, Oguni H, Osawa M, Alonso ME, Delgado-Escueta AV, Inoue Y, Yasui-Furukori N, Kaneko S, Lory P, Yamakawa K (2007) Mutational analysis of CACNA1G in idiopathic generalized epilepsy. Hum Mutat 28:524–525PubMedCrossRefGoogle Scholar
  52. Song I, Kim D, Choi S, Sun M, Kim Y, Shin HS (2004) Role of the alpha1G T-type calcium channel in spontaneous absence seizures in mutant mice. J Neurosci 24:5249–5257PubMedCrossRefGoogle Scholar
  53. Steriade M (1974) Interneuronal epileptic discharges related to spike-and-wave cortical seizures in behaving monkeys. Electroencephalogr Clin Neurophysiol 37:247–263PubMedCrossRefGoogle Scholar
  54. Steriade M, Contreras D (1995) Relations between cortical and thalamic cellular events during transition from sleep patterns to paroxysmal activity. J Neurosci 15:623–642PubMedGoogle Scholar
  55. Steriade M, Deschenes M, Domich L, Mulle C (1985) Abolition of spindle oscillations in thalamic neurons disconnected from nucleus reticularis thalami. J Neurophysiol 54:1473–1497PubMedGoogle Scholar
  56. Steriade M, Domich L, Oakson G (1986) Reticularis thalami neurons revisited: activity changes during shifts in states of vigilance. J Neurosci 6:68–81PubMedGoogle Scholar
  57. Steriade M, Parent A, Pare D, Smith Y (1987) Cholinergic and non-cholinergic neurons of cat basal forebrain project to reticular and mediodorsal thalamic nuclei. Brain Res 408:372–376PubMedCrossRefGoogle Scholar
  58. Steriade M, McCormick DA, Sejnowski TJ (1993) Thalamocortical oscillations in the sleeping and aroused brain. Science 262:679–685PubMedCrossRefGoogle Scholar
  59. Talley EM, Cribbs LL, Lee JH, Daud A, Perez-Reyes E, Bayliss DA (1999) Differential distribution of three members of a gene family encoding low voltage-activated (T-type) calcium channels. J Neurosci 19(6):1895–1911PubMedGoogle Scholar
  60. Talley EM, Solorzano G, Depaulis A, Perez-Reyes E, Bayliss DA (2000) Low-voltage-activated calcium channel subunit expression in a genetic model of absence epilepsy in the rat. Brain Res Mol Brain Res 75:159–165PubMedCrossRefGoogle Scholar
  61. Timofeev I, Grenier F, Steriade M (1998) Spike-wave complexes and fast components of cortically generated seizures. IV Paroxysmal fast runs in cortical and thalamic neurons. J Neurophysiol 80:1495–1513PubMedGoogle Scholar
  62. Tringham E, Powell KL, Cain SM, Kuplast K, Mezeyova J, Weerapura M, Eduljee C, Jiang X, Smith P, Morrison JL, Jones NC, Braine E, Rind G, Fee-Maki M, Parker D, Pajouhesh H, Parmar M, O’Brien TJ, Snutch TP (2012) T-type calcium channel blockers that attenuate thalamic burst firing and suppress absence seizures. Sci Transl Med 4:121ra19PubMedCrossRefGoogle Scholar
  63. Tsakiridou E, Bertollini L, de Curtis M, Avanzini G, Pape HC (1995) Selective increase in T-type calcium conductance of reticular thalamic neurons in a rat model of absence epilepsy. J Neurosci 15:3110–3117PubMedGoogle Scholar
  64. Tscherter A, David F, Ivanova T, Deleuze C, Renger JJ, Uebele VN, Shin HS, Bal T, Leresche N, Lambert RC (2011) Minimal alterations in T-type calcium channel gating markedly modify physiological firing dynamics. J Physiol 589:1707–1724PubMedCentralPubMedCrossRefGoogle Scholar
  65. Vitko I, Chen Y, Arias JM, Shen Y, Wu XR, Perez-Reyes E (2005) Functional characterization and neuronal modeling of the effects of childhood absence epilepsy variants of CACNA1H, a T-type calcium channel. J Neurosci 25:4844–4855PubMedCrossRefGoogle Scholar
  66. Wang J, Zhang Y, Liang J, Pan H, Wu H, Xu K, Liu X, Jiang Y, Shen Y, Wu X (2006) CACNA1I is not associated with childhood absence epilepsy in the Chinese Han population. Pediatr Neurol 35:187–190PubMedCrossRefGoogle Scholar
  67. Westenbroek RE, Sakurai T, Elliott EM, Hell JW, Starr TV, Snutch TP, Catterall WA (1995) Immunochemical identification and subcellular distribution of the alpha 1A subunits of brain calcium channels. J Neurosci 15:6403–6418PubMedGoogle Scholar
  68. Zhang Y, Mori M, Burgess DL, Noebels JL (2002) Mutations in high-voltage-activated calcium channel genes stimulates low-voltage-activated currents in mouse thalamic relay neurons. J Neurosci 22:6362–6371PubMedGoogle Scholar
  69. Zhang Y, Vilaythong AP, Yoshor D, Noebels JL (2004) Elevated thalamic low-voltage-activated currents precede the onset of absence epilepsy in the SNAP25-deficient mouse mutant coloboma. J Neurosci 24:5239–5248PubMedCrossRefGoogle Scholar

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© Springer-Verlag Wien 2015

Authors and Affiliations

  1. 1.Department of PediatricsUniversity of Illinois at ChicagoPeoriaUSA

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