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  • Review Article
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Childhood absence epilepsy: Genes, channels, neurons and networks

Nature Reviews Neuroscience volume 3, pages 371–382 (2002)Cite this article

Key Points

  • Absence seizures are a non-convulsive form of epilepsy that is characterized by a sudden, brief impairment of consciousness. In the electroencephalogram (EEG), absence seizures are accompanied by generalized, synchronous, bilateral spike and slow-wave discharges (SWDs). In childhood absence epilepsy (CAE), the seizures start between 3 and 8 years of age, have a high daily frequency and cannot be induced by sensory stimuli. Most children with CAE show spontaneous remission around adolescence.

  • Most of the genetic studies of CAE have failed to identify its genetic basis. Only two mutations have been discovered in people with CAE and additional neurological disorders; these affect the gene GABRG2, which encodes a GABA (γ-aminobutyric acid) receptor subunit, and CACNA1A, which codes for a subtype of Ca2+ channel. Large-scale genome scans have highlighted several susceptibility loci; establishing the importance of these loci to CAE will require identification of the corresponding mutations.

  • Spontaneous mutations in mice have resulted in animals that serve as models of absence seizures and ataxia. These mutants, which include tottering, lethargic, stargazer, mocha, slow-wave-epilepsy and ducky, develop SWDs and behavioural arrest. In most cases, the mutation affects a Ca2+ channel subunit. A causative link between these mutations and the SWD phenotype remains to be established.

  • In addition to the mouse models, several rat genetic models of absence seizures have been developed. These include the GAERS (genetic absence epilepsy rats from Strasbourg) and the WAG/Rij (Wistar albino Glaxo from Rijswijk) rats. So far, no systematic attempt to identify the genetic basis of the phenotype of these rodents has been undertaken.

  • Several clinical and experimental findings have challenged the classical view of SWDs as generalized EEG paroxysms in favour of a 'focal' cortical origin. However, this view does not imply a localized cortical defect, as the lower threshold for the initiation of the discharges could simply reflect a higher sensitivity of the cortex to an abnormality that is expressed in both cortical and subcortical areas.

  • From the cellular point of view, the EEG abnormalities that are associated with absence seizures involve mainly thalamic and cortical areas — that is, the thalamocortical loop. Studies in animal models have begun to establish the specific involvement of each cellular element of this loop in the expression of these seizures.

  • Genetic and pathophysiological studies in models of absence seizures will help to identify more clearly the mechanisms that underlie SWDs and other electrophysiological abnormalities. Although more stringent classifications of CAE would make it more difficult to select suitable patients for analysis, they could also facilitate the discovery of the genetic traits of CAE.

Abstract

Childhood absence epilepsy is an idiopathic, generalized non-convulsive epilepsy with a multifactorial genetic aetiology. Molecular-genetic analyses of affected human families and experimental models, together with neurobiological investigations, have led to important breakthroughs in the identification of candidate genes and loci, and potential pathophysiological mechanisms for this type of epilepsy. Here, we review these results, and compare the human and experimental phenotypes that have been investigated. Continuing efforts and comparisons of this type will help us to elucidate the multigenetic traits and pathophysiology of this form of generalized epilepsy.

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Figure 1: Spike and slow-wave discharges of childhood absence epilepsy.
Figure 2: Overlap of the complex phenotypes of most common idiopathic generalized epilepsies.
Figure 3: Intracellular counterparts of spontaneous slow-wave discharges in a rat genetic model of absence siezures.
Figure 4: Hypersynchronous activity in an isolated thalamic network.

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References

  1. Panayiotopoulos, C. P. in Epilepsy: a Comprehensive Textbook (eds Engel, J. Jr & Pedley, T. A.) 2327–2346 (Lippincott–Raven, Philadelphia, 1997).A comprehensive clinical review of absence epilepsies. This and reference 4 contain detailed arguments and data in favour of a potential classification of CAE subtypes.

    Google Scholar 

  2. Avoli, M., Rogawski, M. A. & Avanzini, G. Generalized epileptic disorders: an update. Epilepsia 42, 445–457 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 30, 389–399 (1989).

  4. Hirsch, E., Blanc-Platier, A. & Marescaux, C. in Idiopathic Generalized Epilepsies: Clinical, Experimental and Genetic Aspects (eds Malafosse, P. et al.) 87–93 (John Libbey, London, 1994).

    Google Scholar 

  5. Panayiotopoulos, C. P. Treatment of typical absence seizures and related epileptic syndromes. Paediatr. Drugs 3, 379–403 (2001).

    Article  CAS  PubMed  Google Scholar 

  6. Loiseau, P. & Duche, B. in Typical Absences and Related Epileptic Syndromes (eds Duncan, J. S. & Panayiotopoulos, C. P.) 152–160 (Churchill Livingstone, London, 1995).

    Google Scholar 

  7. Janz, D., Beck-Mannagetta, G. & Sander, T. Do idiopathic generalized epilepsies share a common susceptibility gene? Neurology 42, 48–55 (1992).

    CAS  PubMed  Google Scholar 

  8. Berkovic, S. F., Andermann, F., Andermann, E. & Gloor, P. Concepts of absence epilepsies: discrete syndromes or biological continuum? Neurology 37, 993–1000 (1987).

    Article  CAS  PubMed  Google Scholar 

  9. Loiseau, J. et al. Survey of seizure disorders in the French southwest. I. Incidence of epileptic syndromes. Epilepsia 31, 391–396 (1990).

    Article  CAS  PubMed  Google Scholar 

  10. Sander, J. W. A. S. Typical Absences and Related Epileptic Syndromes (eds Duncan, J. S. & Panayiotopoulos, C. P.) 135–144 (Churchill Livingstone, London, 1995).

    Google Scholar 

  11. Desguerre, I. et al. in Idiopathic Generalized Epilepsies: Clinical, Experimental and Genetic Aspects (eds Malafosse, P. et al.) 19–25 (John Libbey, London, 1994).

    Google Scholar 

  12. Rocca, W. A., Sharbrough, F. W., Hauser, W. A., Annegers, J. F. & Schoenberg, B. S. Risk factors for absence seizures: a population-based case–control study in Rochester, Minnesota. Neurology 37, 1309–1314 (1987).

    Article  CAS  PubMed  Google Scholar 

  13. Meencke, H. J. in Typical Absences and Related Epileptic Syndromes (eds Duncan, J. S. & Panayiotopoulos, C. P.) 122–132 (Churchill Livingstone, London, 1995).

    Google Scholar 

  14. Woermann, F. G., Sisodiya, S. M., Free, S. L. & Duncan, J. S. Quantitative MRI in patients with idiopathic generalized epilepsy. Evidence of widespread cerebral structural changes. Brain 121, 1661–1667 (1998).

    Article  PubMed  Google Scholar 

  15. Savic, I., Pauli, S., Thorell, J. O. & Blomqvist, G. In vivo demonstration of altered benzodiazepine receptor density in patients with generalised epilepsy. J. Neurol. Neurosurg. Psychiatry 57, 797–804 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Berkovic, S. F. in Epilepsy: a Comprehensive Textbook (eds Engel, J. Jr & Pedley, T. A.) 217–224 (Lippincott–Raven, Philadelphia, 1998).

    Google Scholar 

  17. Bianchi, A. & The Italian League Against Epilepsy Collaborative Group in Typical Absences and Related Epileptic Syndromes (eds Duncan, J. S. & Panayiotopoulos, C. P.) 328–337 (Churchill Livingstone, London, 1995).

    Google Scholar 

  18. Metrakos, K. & Metrakos, J. D. Genetics of convulsive disorder. II. Genetic and electroencephalographic studies in centrencephalic epilepsy. Neurology 11, 464–483 (1961).

    Article  Google Scholar 

  19. Rogawski, M. A. KCNQ2/KCNQ3 K+ channels and the molecular pathogenesis of epilepsy: implications for therapy. Trends Neurosci. 23, 393–398 (2000).

    Article  CAS  PubMed  Google Scholar 

  20. Robinson, R. & Gardiner, M. Genetics of childhood epilepsy. Arch. Dis. Child. 82, 121–125 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Steinlein, O. K. & Noebels, J. L. Ion channels and epilepsy in man and mouse. Curr. Opin. Genet. Dev. 10, 286–291 (2000).

    Article  CAS  PubMed  Google Scholar 

  22. Wallace, R. H. et al. Mutant GABAA receptor γ2-subunit in childhood absence epilepsy and febrile seizures. Nature Genet. 28, 49–52 (2001).The first identification of a GABA A receptor gene mutation in subjects with CAE and febrile seizures.

    CAS  PubMed  Google Scholar 

  23. Baulac, S. et al. First genetic evidence of GABAA receptor dysfunction in epilepsy: a mutation in the γ2-subunit gene. Nature Genet. 28, 46–48 (2001).

    CAS  PubMed  Google Scholar 

  24. Sander, T. et al. Exclusion of linkage between idiopathic generalized epilepsies and the GABAA receptor α1 and β2 subunit gene cluster on chromosome 5. Epilepsy Res. 23, 235–244 (1996).

    Article  CAS  PubMed  Google Scholar 

  25. Sander, T. et al. Linkage analysis between idiopathic generalized epilepsies and the GABAA receptor α5, β3 and γ3 subunit gene cluster on chromosome 15. Acta Neurol. Scand. 96, 1–7 (1997).

    Article  CAS  PubMed  Google Scholar 

  26. Feucht, M. et al. Possible association between childhood absence epilepsy and the gene encoding GABRB3. Biol. Psychiatry 46, 997–1002 (1999).

    Article  CAS  PubMed  Google Scholar 

  27. Huntsman, M. M., Porcello, D. M., Homanics, G. E., DeLorey, T. M. & Huguenard, J. R. Reciprocal inhibitory connections and network synchrony in the mammalian thalamus. Science 283, 541–543 (1999).Using knockout mice, the authors show for the first time that removal of a GABA A receptor subunit in NRT neurons leads to decreased intra-NRT GABA A -receptor-mediated inhibition and hypersynchronous activity in an isolated thalamic network.

    Article  CAS  PubMed  Google Scholar 

  28. Crunelli, V. & Leresche, N. A role for GABAB receptors in excitation and inhibition of thalamocortical cells. Trends Neurosci. 14, 16–21 (1991).

    Article  CAS  PubMed  Google Scholar 

  29. Blumenfeld, H. & McCormick, D. A. Corticothalamic inputs control the pattern of activity generated in thalamocortical networks. J. Neurosci. 20, 5153–5162 (2000).This and reference 115 provide solid evidence that strong cortical input to an isolated thalamus can switch intrathalamic oscillations from a fast (10-Hz) to a slow (3-Hz) rhythm.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hosford, D. A. et al. Neural network of structures in which GABAB receptors regulate absence seizures in the lethargic (lh/lh) mouse model. J. Neurosci. 15, 7367–7376 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Snead, O. C. Evidence for GABAB-mediated mechanisms in experimental generalized absence seizures. Eur. J. Pharmacol. 213, 343–349 (1992).

    Article  CAS  PubMed  Google Scholar 

  32. Danober, L., Deransart, C., Depaulis, A., Vergnes, M. & Marescaux, C. Pathophysiological mechanisms of genetic absence epilepsy in the rat. Prog. Neurobiol. 55, 27–57 (1998).

    Article  CAS  PubMed  Google Scholar 

  33. Sander, T. et al. Association analysis of exonic variants of the gene encoding the GABAB receptor and idiopathic generalized epilepsy. Am. J. Med. Genet. 88, 305–310 (1999).

    Article  CAS  PubMed  Google Scholar 

  34. Jouvenceau, A. et al. Human epilepsy associated with dysfunction of the brain P/Q-type calcium channel. Lancet 358, 801–807 (2001).The first identification of a mutation in the gene that encodes the pore-forming subunit (α1A) of the P/Q-type Ca2+ channel in a proband with absence epilepsy and ataxia.

    Article  CAS  PubMed  Google Scholar 

  35. Escayg, A. et al. Coding and noncoding variation of the human calcium-channel β4-subunit gene CACNB4 in patients with idiopathic generalized epilepsy and episodic ataxia. Am. J. Hum. Genet. 66, 1531–1539 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Sander, T. et al. The gene encoding the α1A-voltage-dependent calcium channel (CACN1A4) is not a candidate for causing common subtypes of idiopathic generalized epilepsy. Epilepsy Res. 29, 115–122 (1998).

    Article  CAS  PubMed  Google Scholar 

  37. Sander, T. et al. Genetic variation of the human μ-opioid receptor and susceptibility to idiopathic absence epilepsy. Epilepsy Res. 39, 57–61 (2000).

    Article  CAS  PubMed  Google Scholar 

  38. Przewlocka, B. et al. Anatomical and functional aspects of μ opioid receptors in epileptic WAG/Rij rats. Epilepsy Res. 29, 167–173 (1998).

    Article  CAS  PubMed  Google Scholar 

  39. Steinlein, O. et al. Possible association of a silent polymorphism in the neuronal nicotinic acetylcholine receptor subunit α4 with common idiopathic generalized epilepsies. Am. J. Med. Genet. 74, 445–449 (1997).

    Article  CAS  PubMed  Google Scholar 

  40. Chioza, B. et al. Failure to replicate association between the gene for the neuronal nicotinic acetylcholine receptor α4 subunit (CHRNA4) and IGE. Am. J. Med. Genet. 96, 814–816 (2000).

    Article  CAS  PubMed  Google Scholar 

  41. Durner, M. et al. Evidence for linkage of adolescent-onset idiopathic generalized epilepsies to chromosome 8 — and genetic heterogeneity. Am. J. Hum. Genet. 64, 1411–1419 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Fong, G. C. et al. Childhood absence epilepsy with tonic–clonic seizures and electroencephalogram 3–4-Hz spike and multispike–slow wave complexes: linkage to chromosome 8q24. Am. J. Hum. Genet. 63, 1117–1129 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Sugimoto, Y. et al. Childhood absence epilepsy in 8q24: refinement of candidate region and construction of physical map. Genomics 68, 264–272 (2000).

    Article  CAS  PubMed  Google Scholar 

  44. Zara, F. et al. Mapping of genes predisposing to idiopathic generalized epilepsy. Hum. Mol. Genet. 4, 1201–1207 (1995).

    Article  CAS  PubMed  Google Scholar 

  45. Sugimoto, Y. et al. T-STAR gene: fine mapping in the candidate region for childhood absence epilepsy on 8q24 and mutational analysis in patients. Epilepsy Res. 46, 139–144 (2001).

    Article  CAS  PubMed  Google Scholar 

  46. Kananura, C. et al. Tandem pore domain K+-channel TASK-3 (KCNK9) and idiopathic absence epilepsies. Am. J. Med. Genet. 114, 227–229 (2002).

    Article  PubMed  Google Scholar 

  47. Morita, R. et al. JH8, a gene highly homologous to the mouse jerky gene, maps to the region for childhood absence epilepsy on 8q24. Biochem. Biophys. Res. Commun. 248, 307–314 (1998).

    Article  CAS  PubMed  Google Scholar 

  48. Morita, R. et al. Exclusion of the JRK/JH8 gene as a candidate for human childhood absence epilepsy mapped on 8q24. Epilepsy Res. 37, 151–158 (1999).

    Article  CAS  PubMed  Google Scholar 

  49. Haug, K. et al. Mutation screening of the chromosome 8q24.3-human activity-regulated cytoskeleton-associated gene (ARC) in idiopathic generalized epilepsy. Mol. Cell. Probes 14, 255–260 (2000).

    Article  CAS  PubMed  Google Scholar 

  50. Moore, T. et al. Polymorphism analysis of JRK/JH8, the human homologue of mouse jerky, and description of a rare mutation in a case of CAE evolving to JME. Epilepsy Res. 46, 157–167 (2001).

    Article  CAS  PubMed  Google Scholar 

  51. Delgado-Escueta, A. V. et al. Mapping and positional cloning of common idiopathic generalized epilepsies: juvenile myoclonus epilepsy and childhood absence epilepsy. Adv. Neurol. 79, 351–374 (1999).

    CAS  PubMed  Google Scholar 

  52. Sander, T. et al. Genome search for susceptibility loci of common idiopathic generalised epilepsies. Hum. Mol. Genet. 9, 1465–1472 (2000).

    Article  CAS  PubMed  Google Scholar 

  53. Durner, M. et al. Genome scan of idiopathic generalized epilepsy: evidence for major susceptibility gene and modifying genes influencing the seizure type. Ann. Neurol. 49, 328–335 (2001).

    Article  CAS  PubMed  Google Scholar 

  54. Frankel, W. N. Detecting genes in new and old mouse models for epilepsy: a prospectus through the magnifying glass. Epilepsy Res. 36, 97–110 (1999).

    Article  CAS  PubMed  Google Scholar 

  55. Burgess, D. L. & Noebels, J. L. Single gene defects in mice: the role of voltage-dependent calcium channels in absence models. Epilepsy Res. 36, 111–122 (1999).This and reference 21 provide a concise and essential overview of the genetic mouse models of absence epilepsy and ataxia, and their relevance to human absence epilepsy and other neurological disorders.

    Article  CAS  PubMed  Google Scholar 

  56. Crunelli, V. & Leresche, N. Block of thalamic T-type Ca2+ channels by ethosuximide is not the entire story. Epilepsy Curr. 2, 53–56 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Fletcher, C. F. et al. Absence epilepsy in tottering mutant mice is associated with calcium channel defects. Cell 87, 607–617 (1996).This work describes the identification of the single gene mutation (in the Ca2+ channel α1A subunit) of the tottering mouse, a model of absence seizures and ataxia.

    Article  CAS  PubMed  Google Scholar 

  58. Burgess, D. L., Jones, J. M., Meisler, M. H. & Noebels, J. L. Mutation of the Ca2+ channel β subunit gene Cchb4 is associated with ataxia and seizures in the lethargic (lh) mouse. Cell 88, 385–392 (1997).This work describes the identification of the single gene mutation (in the Ca2+ channel β4 subunit) of the lethargic mouse, a model of absence seizures and ataxia.

    Article  CAS  PubMed  Google Scholar 

  59. Chen, L. et al. Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms. Nature 408, 936–943 (2000).

    Article  CAS  PubMed  Google Scholar 

  60. Ophoff, R. A. et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 87, 543–552 (1996).

    Article  CAS  PubMed  Google Scholar 

  61. Denier, C. et al. High prevalence of CACNA1A truncations and broader clinical spectrum in episodic ataxia type 2. Neurology 52, 1816–1821 (1999).

    Article  CAS  PubMed  Google Scholar 

  62. Jun, K. et al. Ablation of P/Q-type Ca2+ channel currents, altered synaptic transmission, and progressive ataxia in mice lacking the α1A-subunit. Proc. Natl Acad. Sci. USA 96, 15245–15250 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Fletcher, C. F. et al. Dystonia and cerebellar atrophy in Cacna1a null mice lacking P/Q calcium channel activity. FASEB J. 15, 1288–1290 (2001).References 62 and 63 show that knockout of the gene that encodes the pore-forming subunit (α1A) of P/Q-type Ca2+ channels leads to a mouse phenotype of absence seizures, dystonia, ataxia and cerebellar atrophy.

    Article  CAS  PubMed  Google Scholar 

  64. Song, I., Kim, D., Jun, K. & Shin, H. S. Role of T-type calcium channels in the genesis of absence seizure in the mutant mice for α1A, the pore-forming subunit of the P/Q-type calcium channel. Soc. Neurosci. Abstr. 27, 151.21 (2001).

    Google Scholar 

  65. Zhang, Y. & Noebles, J. L. Altered calcium currents in thalamocortical relay cells of mouse absence models with mutations of α1A and β4 calcium channel subunits. Soc. Neurosci. Abstr. 27, 151.16 (2001).

    Google Scholar 

  66. Tsakiridou, E., Bertollini, L., de Curtis, M., Avanzini, G. & Pape, H. C. Selective increase in T-type calcium conductance of reticular thalamic neurons in a rat model of absence epilepsy. J. Neurosci. 15, 3110–3117 (1995).The first demonstration, in a rat genetic model of absence epilepsy, of an increase in a voltage-dependent current before seizure onset.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Coenen, A. M., Drinkenburg, W. H., Inoue, M. & van Luijtelaar, E. L. Genetic models of absence epilepsy, with emphasis on the WAG/Rij strain of rats. Epilepsy Res. 12, 75–86 (1992).

    Article  CAS  PubMed  Google Scholar 

  68. Drinkenburg, W. H. I. M., Van Luijtelaar, E. L. J. M. & Coenen, A. M. L. in Memory and Awareness in Anesthesia III (eds Bonke, B., Bovill, J. G. & Moerman, N.) 186–196 (Van Gorcum, Assen, The Netherlands, 1996).

    Google Scholar 

  69. Holter, J. L., Humphries, A., Crunelli, V. & Carter, D. A. Optimisation of methods for selecting candidate genes from cDNA array screens: application to rat brain punches and pineal. J. Neurosci. Methods 112, 173–184 (2001).

    Article  CAS  PubMed  Google Scholar 

  70. Niedermeyer, E. Primary (idiopathic) generalized epilepsy and underlying mechanisms. Clin. Electroencephalogr. 27, 1–21 (1996).

    Article  CAS  PubMed  Google Scholar 

  71. Gibbs, F. A. & Gibbs, E. L. Atlas of Electroencephalography 2nd edn Vol. 2 (Addison–Wesley, Cambridge, UK,1952).

    Google Scholar 

  72. Bancaud, J. in The Physiopathogenesis of the Epilepsies (eds Gastaut, H., Jasper, H., Bancaud, J. & Waltregny, C. C.) 158–185 (Thomas, Springfield, Illinois,1969).

    Google Scholar 

  73. Hunter, J. & Jasper, H. H. Effects of thalamic stimulation on unanesthetized animals. Electroencephalogr. Clin. Neurophysiol. 1, 305–324 (1949).

    CAS  PubMed  Google Scholar 

  74. Jasper, H. H. & Droogleever-Fortuyn, J. Experimental studies of the functional anatomy of petit mal epilepsy. Res. Publ. Assoc. Res. Nerve Ment. Dis. 26, 272–298 (1947).

    Google Scholar 

  75. Gloor, P. & Fariello, R. G. Generalized epilepsy: some of its cellular mechanisms differ from those of focal epilepsy. Trends Neurosci. 11, 63–68 (1988).

    Article  CAS  PubMed  Google Scholar 

  76. Ferri, R., Iliceto, G. & Carlucci, V. Topographic EEG mapping of 3/s spike-and-wave complexes during absence seizures. Ital. J. Neurol. Sci. 16, 541–547 (1995).

    Article  CAS  PubMed  Google Scholar 

  77. Steriade, M. & Amzica, F. Dynamic coupling among neocortical neurons during evoked and spontaneous spike–wave seizure activity. J. Neurophysiol. 72, 2051–2069 (1994).

    Article  CAS  PubMed  Google Scholar 

  78. Meeren, H. K., Pijn, J. P., Van Luijtelaar, E. L., Coenen, A. M. & Lopes da Silva, F. H. Cortical focus drives widespread corticothalamic networks during spontaneous absence seizures in rats. J. Neurosci. 22, 1480–1495 (2002).Using an established model of absence seizures, this paper provided the first demonstration that spontaneous, genetically determined SWDs start in a restricted cortical area before spreading to other cortical regions, and later to thalamic structures.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Neckelmann, D., Amzica, F. & Steriade, M. Spike–wave complexes and fast components of cortically generated seizures. III. Synchronizing mechanisms. J. Neurophysiol. 80, 1480–1494 (1998).

    Article  CAS  PubMed  Google Scholar 

  80. Shouse, M. N. & Martins da Silva, A. in Epilepsy: a Comprehensive Textbook (eds Engel, J. Jr & Pedley, T. A.) 1917–1927 (Lippincott–Raven, Philadelphia, 1998).

    Google Scholar 

  81. Horita, H. Epileptic seizures and sleep–wake rhythm. Psychiatry Clin. Neurosci. 55, 171–172 (2001).

    Article  CAS  PubMed  Google Scholar 

  82. Steriade, M., McCormick, D. A. & Sejnowski, T. J. Thalamocortical oscillations in the sleeping and aroused brain. Science 262, 679–685 (1993).

    Article  CAS  PubMed  Google Scholar 

  83. Pinault, D. et al. Intracellular recordings in thalamic neurones during spontaneous spike and wave discharges in rats with absence epilepsy. J. Physiol. (Lond.) 509, 449–456 (1998).

    Article  CAS  Google Scholar 

  84. Slaght, S. J., Leresche, N., Deniau, J.-M., Crunelli, V. & Charpier, S. Activity of thalamic reticular neurons during spontaneous genetically determined spike and wave discharges. J. Neurosci. 22, 2323–2334 (2002).The first description of the intracellularly recorded activity in NRT neurons during spontaneous SWDs in a genetic model of absence seizures, highlighting the lack of hyperpolarizing GABA A -receptor-mediated IPSPs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Yeni, S. N., Kabasakal, L., Yalcinkaya, C., Nisli, C. & Dervent, A. Ictal and interictal SPECT findings in childhood absence epilepsy. Seizure 9, 265–269 (2000).

    Article  CAS  PubMed  Google Scholar 

  86. Williams, D. A. A study of thalamic and cortical rhythms in petit mal. Brain 76, 56–69 (1953).

    Article  Google Scholar 

  87. Velasco, M., Velasco, F., Velasco, A. L., Lujan, M. & Vazquez del Mercado, J. Epileptiform EEG activities of the centromedian thalamic nuclei in patients with intractable partial motor, complex partial, and generalized seizures. Epilepsia 30, 295–306 (1989).

    Article  CAS  PubMed  Google Scholar 

  88. Snead, O. C. Basic mechanisms of generalized absence seizures. Ann. Neurol. 37, 146–157 (1995).

    Article  PubMed  Google Scholar 

  89. Iannetti, P. et al. Ictal single photon emission computed tomography in absence seizures: apparent implication of different neuronal mechanisms. J. Child. Neurol. 16, 339–344 (2001).

    Article  CAS  PubMed  Google Scholar 

  90. Prevett, M. C., Duncan, J. S., Jones, T., Fish, D. R. & Brooks, D. J. Demonstration of thalamic activation during typical absence seizures using H215O and PET. Neurology 45, 1396–1402 (1995).The first imaging evidence that thalamic structures are involved in human absence seizures.

    Article  CAS  PubMed  Google Scholar 

  91. Giaretta, D., Avoli, M. & Gloor, P. Intracellular recordings in pericruciate neurons during spike and wave discharges of feline generalized penicillin epilepsy. Brain Res. 405, 68–79 (1987).

    Article  CAS  PubMed  Google Scholar 

  92. Charpier, S. et al. On the putative contribution of GABAB receptors to the electrical events occurring during spontaneous spike and wave discharges. Neuropharmacology 38, 1699–1706 (1999).

    Article  CAS  PubMed  Google Scholar 

  93. Ayala, G. F. The paroxysmal depolarizing shift. Prog. Clin. Biol. Res. 124, 15–21 (1983).

    CAS  PubMed  Google Scholar 

  94. Pumain, R., Louvel, J., Gastard, M., Kurcewicz, I. & Vergnes, M. Responses to N-methyl-d-aspartate are enhanced in rats with petit mal-like seizures. J Neural Transm Suppl 35, 97–108 (1992).

    CAS  PubMed  Google Scholar 

  95. Luhmann, H. J., Mittmann, T., Van Luijtelaar, G. & Heinemann, U. Impairment of intracortical GABAergic inhibition in a rat model of absence epilepsy. Epilepsy Res. 22, 43–51 (1995).

    Article  CAS  PubMed  Google Scholar 

  96. Timofeev, I., Grenier, F. & Steriade, M. Spike–wave complexes and fast components of cortically generated seizures. IV. Paroxysmal fast runs in cortical and thalamic neurons. J. Neurophysiol. 80, 1495–1513 (1998).

    Article  CAS  PubMed  Google Scholar 

  97. Bal, T., Von Krosigk, M. & McCormick, D. A. Role of the ferret perigeniculate nucleus in the generation of synchronized oscillations in vitro. J. Physiol. (Lond.) 483, 665–685 (1995).

    Article  CAS  Google Scholar 

  98. Talley, E. M., Solorzano, G., Depaulis, A., Perez-Reyes, E. & Bayliss, D. A. Low-voltage-activated calcium channel subunit expression in a genetic model of absence epilepsy in the rat. Brain Res. Mol. Brain Res. 75, 159–165 (2000).

    Article  CAS  PubMed  Google Scholar 

  99. Landisman, C. E. et al. Electrical synapses in the thalamic reticular nucleus. J. Neurosci. 22, 1002–1009 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Caddick, S. J. et al. Excitatory but not inhibitory synaptic transmission is reduced in lethargic (Cacnb4lh) and tottering (Cacna1atg) mouse thalami. J. Neurophysiol. 81, 2066–2074 (1999).

    Article  CAS  PubMed  Google Scholar 

  101. Steriade, M. & Contreras, D. Spike–wave complexes and fast components of cortically generated seizures. I. Role of neocortex and thalamus. J. Neurophysiol. 80, 1439–1455 (1998).

    Article  CAS  PubMed  Google Scholar 

  102. Avoli, M. & Gloor, P. Role of the thalamus in generalized penicillin epilepsy: observations on decorticated cats. Exp. Neurol. 77, 386–402 (1982).

    Article  CAS  PubMed  Google Scholar 

  103. Avanzini, G., de Curtis, M., Franceschetti, S., Sancini, G. & Spreafico, R. Cortical versus thalamic mechanisms underlying spike and wave discharges in GAERS. Epilepsy Res. 26, 37–44 (1996).

    Article  CAS  PubMed  Google Scholar 

  104. Steriade, M. & Contreras, D. Relations between cortical and thalamic cellular events during transition from sleep patterns to paroxysmal activity. J. Neurosci. 15, 623–642 (1995).The first demonstration that most thalamocortical neurons are silent during spontaneous SWDs in cats. With reference 83 , this reference clearly indicates that the inhibition of these neurons is responsible for the subject's unresponsiveness during absence seizures.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Avoli, M., Gloor, P., Kostopoulos, G. & Gotman, J. An analysis of penicillin-induced generalized spike and wave discharges using simultaneous recordings of cortical and thalamic single neurons. J. Neurophysiol. 50, 819–837 (1983).

    Article  CAS  PubMed  Google Scholar 

  106. Timofeev, I., Grenier, F. & Steriade, M. Spike–wave complexes and fast components of cortically generated seizures. IV. Paroxysmal fast runs in cortical and thalamic neurons. J. Neurophysiol. 80, 1495–1513 (1998).

    Article  CAS  PubMed  Google Scholar 

  107. Golshani, P., Liu, X. B. & Jones, E. G. Differences in quantal amplitude reflect GluR4-subunit number at corticothalamic synapses on two populations of thalamic neurons. Proc. Natl Acad. Sci. USA 98, 4172–4177 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Slaght, S. J., Charpier, S., Leresche, N., Deniau, J.-M. & Crunelli, V. Firing properties of thalamic neurones during spike and wave discharges in the GAERS genetic model of absence epilepsy. Soc. Neurosci. Abstr. 27, 969.7 (2001).

    Google Scholar 

  109. Kim, D. et al. Lack of the burst firing of thalamocortical relay neurons and resistance to absence seizures in mice lacking α1G T-type Ca2+ channels. Neuron 31, 35–45 (2001).The first demonstration, using transgenic techniques, that the gene that encodes the pore-forming subunit (α1G) of the T-type Ca2+ channel is crucial in the generation of pharmacologically induced absence seizures.

    Article  CAS  PubMed  Google Scholar 

  110. Snead, O. C. Pharmacological models of generalized absence seizures in rodents. J Neural Transm Suppl 35, 7–19 (1992).

    PubMed  Google Scholar 

  111. De la Pena, E. & Geijo-Barrientos, E. Laminar localization, morphology, and physiological properties of pyramidal neurons that have the low-threshold calcium current in the guinea-pig medial frontal cortex. J. Neurosci. 16, 5301–5311 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Williams, S. R., Toth, T. I., Turner, J. P., Hughes, S. W. & Crunelli, V. The 'window' component of the low threshold Ca2+ current produces input signal amplification and bistability in cat and rat thalamocortical neurones. J. Physiol. (Lond.) 505, 689–705 (1997).

    Article  CAS  Google Scholar 

  113. Hughes, S. W., Cope, D. W., Blethyn, K. & Crunelli, V. Cellular mechanisms of the slow (<1 Hz) oscillation in thalamocortical neurons in vitro. Neuron 33, 947–958 (2002).

    Article  CAS  PubMed  Google Scholar 

  114. Staak, R. & Pape, H. C. Contribution of GABAA and GABAB receptors to thalamic neuronal activity during spontaneous absence seizures in rats. J. Neurosci. 21, 1378–1384 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Bal, T., Debay, D. & Destexhe, A. Cortical feedback controls the frequency and synchrony of oscillations in the visual thalamus. J. Neurosci. 20, 7478–7488 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Seidenbecher, T. & Pape, H. C. Contribution of intralaminar thalamic nuclei to spike-and-wave-discharges during spontaneous seizures in a genetic rat model of absence epilepsy. Eur. J. Neurosci. 13, 1537–1546 (2001).

    Article  CAS  PubMed  Google Scholar 

  117. Fletcher, C. F. & Frankel, W. N. Ataxic mouse mutants and molecular mechanisms of absence epilepsy. Hum. Mol. Genet. 8, 1907–1912 (1999).

    Article  CAS  PubMed  Google Scholar 

  118. Zhang, Y. F., Gibbs, J. W. & Coulter, D. A. Anticonvulsant drug effects on spontaneous thalamocortical rhythms in vitro: ethosuximide, trimethadione, and dimethadione. Epilepsy Res. 23, 15–36 (1996).

    Article  CAS  PubMed  Google Scholar 

  119. Wells, T. & Carter, D. A. Genetic engineering of neural function in transgenic rodents: towards a comprehensive strategy? J. Neurosci. Methods 108, 111–130 (2001).

    Article  CAS  PubMed  Google Scholar 

  120. Cox, G. A. et al. Sodium/hydrogen exchanger gene defect in slow-wave epilepsy mutant mice. Cell 91, 139–148 (1997).

    Article  CAS  PubMed  Google Scholar 

  121. Castro-Alamancos, M. A. Neocortical synchronized oscillations induced by thalamic disinhibition in vivo. J. Neurosci. 19, RC27 (1999).

  122. Sander, T. et al. Allelic association of juvenile absence epilepsy with a GluR5 kainate receptor gene (GRIK1) polymorphism. Am. J. Med. Genet. 74, 416–421 (1997).

    Article  CAS  PubMed  Google Scholar 

  123. Sander, T. et al. Refinement of map position of the human GluR6 kainate receptor gene (GRIK2) and lack of association and linkage with idiopathic generalized epilepsies. Neurology 45, 1713–1720 (1995).

    Article  CAS  PubMed  Google Scholar 

  124. Goodwin, H. et al. No association found between polymorphisms in genes encoding mGluR7 and mGluR8 and idiopathic generalised epilepsy in a case control study. Epilepsy Res. 39, 27–31 (2000).

    Article  CAS  PubMed  Google Scholar 

  125. Escayg, A. et al. A novel SCN1A mutation associated with generalized epilepsy with febrile seizures plus — and prevalence of variants in patients with epilepsy. Am. J. Hum. Genet. 68, 866–873 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Steinlein, O. K., Stoodt, J., Biervert, C., Janz, D. & Sander, T. The voltage gated potassium channel KCNQ2 and idiopathic generalized epilepsy. Neuroreport 10, 1163–1166 (1999).

    Article  CAS  PubMed  Google Scholar 

  127. Sander, T. et al. Variation of the genes encoding the human glutamate EAAT2, serotonin and dopamine transporters and susceptibility to idiopathic generalized epilepsy. Epilepsy Res. 41, 75–81 (2000).

    Article  CAS  PubMed  Google Scholar 

  128. Haug, K. et al. Association analysis between a regulatory-promoter polymorphism of the human monoamine oxidase A gene and idiopathic generalized epilepsy. Epilepsy Res. 39, 127–132 (2000).

    Article  CAS  PubMed  Google Scholar 

  129. Sander, T. et al. Association analysis of a regulatory promoter polymorphism of the PAX-6 gene with idiopathic generalized epilepsy. Epilepsy Res. 36, 61–67 (1999).

    Article  CAS  PubMed  Google Scholar 

  130. Sander, T. et al. Common subtypes of idiopathic generalized epilepsies: lack of linkage to D20S19 close to candidate loci (EBN1, EEGV1) on chromosome 20. Am. J. Med. Genet. 67, 31–39 (1996).

    Article  CAS  PubMed  Google Scholar 

  131. Marescaux, C., Vergnes, M. & Depaulis, A. Genetic absence epilepsy in rats from Strasbourg — a review. J Neural Transm Suppl 35, 37–69 (1992).

    CAS  PubMed  Google Scholar 

  132. Ingram, E. M., Tessler, S., Bowery, N. G. & Emson, P. C. Glial glutamate transporter mRNAs in the genetically absence epilepsy rat from Strasbourg. Brain Res. Mol. Brain Res. 75, 96–104 (2000).

    Article  CAS  PubMed  Google Scholar 

  133. Midzianovskaia, I. S., Kuznetsova, G. D., Coenen, A. M., Spiridonov, A. M. & Van Luijtelaar, E. L. Electrophysiological and pharmacological characteristics of two types of spike–wave discharges in WAG/Rij rats. Brain Res. 911, 62–70 (2001).

    Article  CAS  PubMed  Google Scholar 

  134. Jando, G. et al. Spike-and-wave epilepsy in rats: sex differences and inheritance of physiological traits. Neuroscience 64, 301–317 (1995).

    Article  CAS  PubMed  Google Scholar 

  135. Noebels, J. L. & Sidman, R. L. Inherited epilepsy: spike–wave and focal motor seizures in the mutant mouse tottering. Science 204, 1334–1336 (1979).

    Article  CAS  PubMed  Google Scholar 

  136. Levitt, P. & Noebels, J. L. Mutant mouse tottering: selective increase of locus ceruleus axons in a defined single-locus mutation. Proc. Natl Acad. Sci. USA 78, 4630–4634 (1981).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Rhyu, I. J., Abbott, L. C., Walker, D. B. & Sotelo, C. An ultrastructural study of granule cell/Purkinje cell synapses in tottering (tg/tg), leaner (tgla/tgla) and compound heterozygous tottering/leaner (tg/tgla) mice. Neuroscience 90, 717–728 (1999).

    Article  CAS  PubMed  Google Scholar 

  138. Hosford, D. A. et al. Studies of the lethargic (lh/lh) mouse model of absence seizures: regulatory mechanisms and identification of the lh gene. Adv. Neurol. 79, 239–252 (1999).

    CAS  PubMed  Google Scholar 

  139. Noebels, J. F. in Idiopathic Generalized Epilepsies (eds Malafosse, A. et al.) 215–225 (John Libbey & Co. Ltd, London, 1994).

    Google Scholar 

  140. Qiao, X. & Noebels, J. L. Developmental analysis of hippocampal mossy fiber outgrowth in a mutant mouse with inherited spike–wave seizures. J. Neurosci. 13, 4622–4635 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Kantheti, P. et al. Mutation in AP-3 δ in the mocha mouse links endosomal transport to storage deficiency in platelets, melanosomes, and synaptic vesicles. Neuron 21, 111–122 (1998).

    Article  CAS  PubMed  Google Scholar 

  142. Noebels, J. F. in Jasper's Basic Mechanisms of the Epilepsies (eds Delgado-Escueta, A. V., Wilson, W. A., Olsen, R. W. & Porter, R. J.) 227–238 (Lippincott Williams & Wilkins, Philadelphia, 1999).

    Google Scholar 

  143. Meier, H. The neuropathology of ducky, a neurological mutation of the mouse. A pathological and preliminary histochemical study. Acta Neuropathol. (Berl.) 11, 15–28 (1968).

    Article  CAS  Google Scholar 

  144. Brodbeck, J. et al. The ducky mutation in Cacna2d2 results in altered Purkinje cell morphology and is associated with the expression of a truncated α2δ2 protein with abnormal function. J. Biol. Chem. 277, 7684–7693 (2002).

    Article  CAS  PubMed  Google Scholar 

  145. Barclay, J. et al. Ducky mouse phenotype of epilepsy and ataxia is associated with mutations in the Cacna2d2 gene and decreased calcium channel current in cerebellar Purkinje cells. J. Neurosci. 21, 6095–6104 (2002).

    Article  Google Scholar 

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Acknowledgements

We wish to thank G. Avanzini, D. A. Carter, J. L. Noebels, T. Panayiotopoulos and R. Spreafico for constructive comments, and S. W. Hughes and J. L. Holter for help in the preparation of the manuscript. Our work on absence epilepsy is supported by the Wellcome Trust, the Centre National de la Recherche Scientifique, the Ministère de la Recherche, and the European Union.

Author information

Authors and Affiliations

  1. School of Bioscience, Cardiff University, Museum Avenue, Cardiff, CF10 3US, Wales, UK

    Vincenzo Crunelli

  2. Neurobiologie des Processus Adaptatifs, UMR CNRS 7102, Université Pierre et Marie Curie, 9 quai St Bernard, Paris, 75252, France

    Nathalie Leresche

Authors
  1. Vincenzo Crunelli
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Correspondence to Vincenzo Crunelli.

Related links

Related links

DATABASES

LocusLink

ARC

CACNA1A

Cacna1g

CACNB4

CHRNA4

CHRNB3

ECA1

GABBR1

GABRA1

GABRA5

GABRB3

GABRG2

GABRG3

JH8

Nhe1

OPRM1

TASK-3

T-STAR

OMIM

childhood absence epilepsy

episodic ataxia type 2

generalized epilepsy with febrile seizures plus

idiopathic generalized epilepsies

juvenile myoclonic epilepsy

spinocerebellar ataxia type 6

FURTHER INFORMATION

Crunelli Research Group

International League Against Epilepsy 

Encyclopedia of Life Sciences

epilepsy

Glossary

GENERALIZED TONIC–CLONIC SEIZURE

A type of seizure that begins with rigidity (tonic phase), followed by repetitive clonic activity of all extremities.

FEBRILE SEIZURE

A generalized seizure that occurs in conjunction with fever.

PROBAND

Usually, the person who serves as the starting point of a genetic study.

PENETRANCE

The proportion of genotypically mutant organisms that show the mutant phenotype. If all genotypically mutant individuals show the mutant phenotype, then the genotype is said to be completely penetrant.

CONCORDANCE

The occurrence of a trait in both of two related individuals, such as twins or siblings.

GENETIC POLYMORPHISM

The simultaneous existence in the same population of two or more genotypes in frequencies that cannot be explained by recurrent mutations.

NUCLEUS RETICULARIS THALAMI

A thalamic nucleus that covers the lateral and anterior aspects of the mammalian thalamus, and almost exclusively contains GABA-producing neurons.

EPISODIC ATAXIA TYPE 2

An autosomal-dominant disorder that is characterized by the recurrence of spells of cerebellar ataxia, usually starting during childhood or adolescence.

PRAXIS-INDUCED SEIZURE

A type of seizure that is induced by performing planned, coordinated movements.

ICTAL

Relating to or occurring during a seizure.

CENTRENCEPHALIC HYPOTHESIS

The idea that generalized SWDs originate in a hypothetical neuronal network — the 'centrencephalon' — that is centred on the upper brainstem and diencephalon, with diffuse cortical projections.

CORTICO-RETICULAR HYPOTHESIS

The idea that generalized SWDs result from an abnormal interaction of ascending inputs from 'midbrain and midline thalamic reticular systems' and a diffusely hyperexcitable coretx.

LENNOX–GASTAUT SYNDROME

A severe form of childhood epilepsy that is characterized by very frequent seizures of several types. Most patients also have severe learning difficulties.

WEST SYNDROME

An epileptic syndrome that is characterized by infantile spasms (generalized seizures), hypsarrhythmia and arrest of psychomotor development at seizure onset.

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Crunelli, V., Leresche, N. Childhood absence epilepsy: Genes, channels, neurons and networks. Nat Rev Neurosci 3, 371–382 (2002). https://doi.org/10.1038/nrn811

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