Single locus mutations in mice expressing generalized spike-wave absence epilepsies

  • Noebels J. L. 
Animal Models Relevant to Human Epilepsies


Studies in mutant mice are beginning to reveal important general principles regarding the heredity of the spike-wave cortical synchronization trait. First, a defect at a single gene locus is sufficient to produce a generalized spike-wave seizure disorder. Second, the EEG pattern itself is genetically heterogeneous, and can arise from mutations in at least five independent loci. Third, the intervening cellular excitability mechanisms underlying the generation of spike-wave cortical discharges are not identical. Fourth, each of the mutant genes gives rise to syndromes that can differ in their seizure frequency, sensitivity to antiepileptic drugs, and severity of the associated neurological phenotype. Fifth, primary defects can be distinguished from secondary cellular alterations resulting from pathological neuronal synchronization. The patterns of these secondary changes vary according to the specific mutant allele, and may give rise to distinctive secondary phenotypes. The reproducibility of these defined genetic models may facilitate age-dependent antiepileptic drug discovery by defining novel targets for therapy at different developmental stages of the seizure disorder.

Key Words

genetic epilepsy mouse mutants stargazer-tottering 


Gli studi sui topi mutanti stanno iniziando a rivelare importanti principi generali, relativi alla ereditarietà del tratto EEG punta-onda. In primo luogo un difetto limitato al locus di un singolo gene è sufficiente a produrre una alterazione epilettogena generalizzata tipo punta-onda. In secondo luogo il quadro EEG è di per sè geneticamente eterogeneo e può originare da mutazioni in almeno cinque loci indipendenti.

In terzo luogo le alterazioni di eccitabilità cellulare che sottendono la generazione di scariche di PO non sono identiche nei vari mutanti.

In quarto luogo ciascuno dei geni mutanti dà luogo a sindromi che possono differire in termini di frequenza critica, sensibilità ai farmaci antiepilettici e severità del quadro fenotipico neurologico associato. In quinto luogo i difetti primari geneticamente determinanti possono essere distinti da alterazioni cellulari secondarie risultanti dalla sincronizzazione neuronale patologica.

I caratteri di queste alterazioni secondarie variano in rapporto allo specifico allele mutante dando luogo a distinti fenotipi secondari. La riproducibilità di questi modelli geneticamente definiti può rendere possibile la scoperta di farmaci antiepilettici ad attività età-dipendente definendo nuovi bersagli terapeutici a vari stadi di sviluppo delle epilessie.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. [1]
    Helekar S.A., Noebels J.L.:Synchronous hippocampal bursting unmasks latent network excitability alterations in an epileptic gene mutation. Proceedings of the National Academy of Science (USA), 88: 4736–4740, 1991.Google Scholar
  2. [2]
    Helekar S.A., Noebels J.L.:A burst dependent excitability defect elicited by potassium at the developmental onset of spike-wave seizures in the tottering mutant. Developmental Brain Research, 65: 205–210, 1992.PubMedGoogle Scholar
  3. [3]
    Helekar S.A., Noebels J.L.:Analysis of voltage-gated and synaptic conductances contributing to a gene-linked prolongation of depolarizing shifts in the epileptic mutant mouse tottering. J. Neurophysiol., 71: 1–10, 1994.PubMedGoogle Scholar
  4. [4]
    Heller A.H., Dichter M.A., Sidman R.L.:Anticonvulsant sensitivity of absence seizures in the tottering mutant mouse. Epilepsia, 25: 25–34, 1983.Google Scholar
  5. [5]
    Hosford D.A., Clark S., Cao Z., Wilson W., Lin F-H, Morisett R.A., Huin A.:The role of GABA B receptor activation in absence seizures of lethargic (lh/lh) mice. Science, 257: 398–401, 1992.PubMedGoogle Scholar
  6. [6]
    Keegan K., Noebels J.L.:In vitro electrophysiology of spontaneous and induced epileptiform discharges reveal increased cortical excitability in the mutant mouse, stargazer. Soc. Neuroscience Abstracts, 19: 1031, 1993.Google Scholar
  7. [7]
    Levitt P., Noebels J.L.:Mutant mouse tottering: selective increase of locus coeruleus axons in a defined single locus mutation. Proc. Nat. Acad. Sci (USA), 78: 4630–4634, 1981.Google Scholar
  8. [8]
    Liu Z., Vergnes M., Depaulis A., Marescaux C.:Involvement of intrathalamic GABA B neurotransmission in the control of absence seizures in the rat. Neuroscience, 48: 87–93, 1992.PubMedGoogle Scholar
  9. [9]
    Nahm W.K., Noebels J.L.:Immediate-early gene protein expression in a mutant mouse model of spike-wave epilepsy, stargazer. Soc. Neuroscience Abstracts, 19: 1030, 1993.Google Scholar
  10. [10]
    Noebels J.L.:Analysis of inherited epilepsy using single locus mutations in mice. Federation Proceedings 38: 3405–2410, 1979.Google Scholar
  11. [11]
    Noebels J.L.:A single gene error in noradrenergic axon growth synchronizes central neurons. Nature 10: 409–411, 1984.Google Scholar
  12. [12]
    Noebels J.L.:Mutational analysis of the inherited epilepsies. In:Basic Mechanisms of the Epilepsies: Molecular and Cellular Approaches. Eds. Delgado-Escueta, A.V., Ward, A.A., Woodbury, D.M. Raven Press, New York, 1986.Google Scholar
  13. [13]
    Noebels J.L., Qiao X., Bronson R.T., Spencer C., Davidsson M.T.:Stargazer: a new neurological mutant in the mouse on chromosome 15 with prolonged cortical seizures. Epilepsy Res., 7: 129–135, 1990.PubMedGoogle Scholar
  14. [14]
    Noebels J.L., Rutecki P.A.:Altered hippocampal network excitability in the hypernoradrenergic mutant mouse tottering. Brain Res., 524: 225–230, 1990.PubMedGoogle Scholar
  15. [15]
    Noebels J.L., Sidman R.L.:Inherited epilepsy: spike-wave and focal motor seizures in the mutant mouse tottering. Science 204: 1334–1336, 1979.PubMedGoogle Scholar
  16. [16]
    Qiao X., Noebels J.L.:genetic heterogeneity of inherited spike-wave epilepsy: two mutant gene loci with independent cerebral excitability defects. Brain Res., 555: 43–50, 1991.PubMedGoogle Scholar
  17. [17]
    Qiao X., Noebels J.L.:GABA A receptor-independent spike-wave epilepsy in the mutant mouse stargazer. Pharmacol. Abstracts., 18: 553, 1992.Google Scholar
  18. [18]
    Qiao X., Noebels J.L.:Elevated BDNF mRNA expression in the hippocampus of an epileptic mutant mouse, stargazer. Soc. Neuroscience Abstracts 19: 1030, 1993.Google Scholar
  19. [19]
    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.PubMedGoogle Scholar
  20. [20]
    Stanfield B.B.:Excessive intra- and supragranular mossy fibers in the dentate gyrus of tottering (tg/tg) mice. Brain Res., 480: 294–299, 1989.PubMedGoogle Scholar
  21. [21]
    Sutula T., Cascino G., Cavazos J., Parada I., Ramirez L.:Mossy fiber synaptic reorganization in the epileptic human temporal lobe. Ann. Neurol., 26: 321–330, 1989.PubMedGoogle Scholar

Copyright information

© Masson Italia Periodici S.r.l. 1995

Authors and Affiliations

  • Noebels J. L. 
    • 1
  1. 1.Developmental Neurogenetics Laboratory Department of Neurology, Section of NeurophysiologyBaylor College of MedicineHoustonUSA

Personalised recommendations