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

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

Abstract

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 

Sommario

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.

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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

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