Caracterização dos parâmetros de sono e dos padrões epileptogênicos e comportamentais de animais geneticamente modificados com disfunções nos canais de sódio Scn8a e Scn1a
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Data
2010
Autores
Papale, Ligia Assumpção [UNIFESP]
Orientadores
Tufik, Sergio [UNIFESP]
Tipo
Tese de doutorado
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Os canais de sódio dependentes de voltagem (CSDV) possuem um papel importante para a regulação da excitabilidade neuronal. Os CSDV SCN1A, SCN2A, SCN3A, e SCN8A, são principalmente expressos no sistema nervoso central. As mutações nos genes SCN1A, SCN2A, SCN3A e SCN8A estão associadas a alterações neuromusculares, instabilidade emocional, retardo cognitivo e epilepsia. Os distúrbios do sono são geralmente associados as crises epilépticas e a instabilidade emocional, assim neste estudo propôs-se a caracterização da arquitetura do sono basal e após 6 horas de privação total de sono em animais com mutação no gene Scn8a. Também se propôs a avaliação dos comportamento de ansiedade, de depressão e de memória, bem como determinar os níveis de corticosterona no início das fases claro e escura. Adicionalmente, caracterizou-se o padrão do sono e da vigília em um modelo animal de epilepsia generalizada com crises febris (do inglês, GEFS+, Generalized Epilepsy with Febrile Seizures Plus), que possuem a mutação R1648H no gene Scn1a ortólogo em camundongos. No primeiro estudo, demonstrou-se que os animais heterozigotos com mutação no gene Scn8a (Scn8amed-jo/+, Scn8amed/+ e Scn8a8J/+) possuíam complexos espícula-onda característicos da crise de ausência. No segundo estudo, demonstrou-se que os animais Scn8amed-jo/+ apresentam um tempo maior do sono de ondas lentas, uma prolongada diminuição do sono paradoxal, uma diminuição dos níveis de corticosterona e melhora de memória espacial em relação aos controles. Por último, o terceiro estudo concluiu que o modelo animal da epilepsia humana GEFS+ apresenta uma arquitetura de sono similar aos controles durante o período basal e rebote. Esses dados sugerem que o gene Scn8a pode ser um gene candidato à epilepsia de ausência em humanos, que os CSDV codificados pelo gene Scn8a possui papel importante no ciclo vigília-sono e que a sua regulação pelos CSDV pode ser especificamente dirigida a um subtipo de CSDV. Em conclusão, estes estudos ampliam o espectro de fenótipos associados com mutações nos genes Scn8a e Scn1a.
Voltage-gated sodium channels (VGSC) play a critical role in the regulation of neuronal excitability. Four VGSC, namely SCN1A, SCN2A, SCN3A, and SCN8A, are primarily expressed in the central nervous system. Mutations in SCN1A, SCN2A, SCN3A, and SCN8A are associated neuromuscular disorders, emotional instability, cognitive delay, and epilepsy. Since epilepsy and emotional instability are often correlated with sleep disorders, we proposed to characterize the baseline sleep pattern as well as the sleep rebound following 6-hours of sleep deprivation in an animal with a missense mutation in the Scn8a gene (Scn8amed-jo/+). We also proposed to examine the anxiety, depression, and memory behavior responses, as well as to identify the corticosterone levels at the beginning of the light and dark phases. Additionally, we proposed to evaluate the sleep and wake cycle in an animal model of generalized epilepsy with febrile seizures plus (GEFS+), which shows the mutation R1648H in the orthologous Scn1a gene in mice. In the first study, we characterized the absence seizure phenotype of Scn8amed-jo/+ and two other Scn8a mutants (Scn8amed/+ and Scn8a8J/+). In the second study, we showed that compared to the wild-type littermates, the Scn8amed-jo/+ mutants experience more non-REM sleep, a chronic impairment of REM sleep generation and quantity, a lowered and flattened diurnal rhythm of corticosterone levels, and improvement of spatial memory. Finally, in the third study, we determined that the animal model of GEFS+ shows unaltered sleep pattern during baseline recording as well as during sleep rebound. These studies suggest that the Scn8a may be an attractive candidate gene for common human absence epilepsy, and also suggest a role of Scn8a sodium channel function in the sleep-wake cycle. Since no sleep abnormalities were observed in the animal model of GEFS+, it also suggest that the regulation of sleep architecture by VGSC appears to be subtype-specific. In conclusion, the studies shown extended the spectrum of phenotypes associated with mutations in Scn8a and Scn1a genes.
Voltage-gated sodium channels (VGSC) play a critical role in the regulation of neuronal excitability. Four VGSC, namely SCN1A, SCN2A, SCN3A, and SCN8A, are primarily expressed in the central nervous system. Mutations in SCN1A, SCN2A, SCN3A, and SCN8A are associated neuromuscular disorders, emotional instability, cognitive delay, and epilepsy. Since epilepsy and emotional instability are often correlated with sleep disorders, we proposed to characterize the baseline sleep pattern as well as the sleep rebound following 6-hours of sleep deprivation in an animal with a missense mutation in the Scn8a gene (Scn8amed-jo/+). We also proposed to examine the anxiety, depression, and memory behavior responses, as well as to identify the corticosterone levels at the beginning of the light and dark phases. Additionally, we proposed to evaluate the sleep and wake cycle in an animal model of generalized epilepsy with febrile seizures plus (GEFS+), which shows the mutation R1648H in the orthologous Scn1a gene in mice. In the first study, we characterized the absence seizure phenotype of Scn8amed-jo/+ and two other Scn8a mutants (Scn8amed/+ and Scn8a8J/+). In the second study, we showed that compared to the wild-type littermates, the Scn8amed-jo/+ mutants experience more non-REM sleep, a chronic impairment of REM sleep generation and quantity, a lowered and flattened diurnal rhythm of corticosterone levels, and improvement of spatial memory. Finally, in the third study, we determined that the animal model of GEFS+ shows unaltered sleep pattern during baseline recording as well as during sleep rebound. These studies suggest that the Scn8a may be an attractive candidate gene for common human absence epilepsy, and also suggest a role of Scn8a sodium channel function in the sleep-wake cycle. Since no sleep abnormalities were observed in the animal model of GEFS+, it also suggest that the regulation of sleep architecture by VGSC appears to be subtype-specific. In conclusion, the studies shown extended the spectrum of phenotypes associated with mutations in Scn8a and Scn1a genes.
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Citação
PAPALE, Ligia Assumpção. Caracterização dos parâmetros de sono e dos padrões epileptogênicos e comportamentais de animais geneticamente modificados com disfunções nos canais de sódio Scn8a e Scn1a. 2010.128f. Tese (Doutorado) - Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, 2010.