Altered sleep regulation in a mouse model of SCN1A-derived genetic epilepsy with febrile seizures plus (GEFS+)

Altered sleep regulation in a mouse model of SCN1A-derived genetic epilepsy with febrile seizures plus (GEFS+)

Autor Papale, Ligia A. Autor UNIFESP Google Scholar
Makinson, Christopher D. Google Scholar
Ehlen, J. Christopher Google Scholar
Tufik, Sergio Autor UNIFESP Google Scholar
Decker, Michael J. Google Scholar
Paul, Ketema N. Google Scholar
Escayg, Andrew Google Scholar
Instituição Emory Univ
Universidade Federal de São Paulo (UNIFESP)
Morehouse Sch Med
Georgia State Univ
Resumo Purpose Mutations in the voltage-gated sodium channel (VGSC) gene SCN1A are responsible for a number of epilepsy disorders, including genetic epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome. in addition to seizures, patients with SCN1A mutations often experience sleep abnormalities, suggesting that SCN1A may also play a role in the neuronal pathways involved in the regulation of sleep. However, to date, a role for SCN1A in the regulation of sleep architecture has not been directly examined. To fill this gap, we tested the hypothesis that SCN1A contributes to the regulation of sleep architecture, and by extension, that SCN1A dysfunction contributes to the sleep abnormalities observed in patients with SCN1A mutations. Methods Using immunohistochemistry we first examined the expression of mouse Scn1a in regions of the mouse brain that are known to be involved in seizure generation and sleep regulation. Next, we performed detailed analysis of sleep and wake electroencephalography (EEG) patterns during 48 continuous hours of baseline recordings in a knock-in mouse line that expresses the human SCN1A GEFS+ mutation R1648H (RH mutants). We also characterized the sleepwake pattern following 6h of sleep deprivation. Key Findings Immunohistochemistry revealed broad expression of Scn1a in the neocortex, hippocampus, hypothalamus, thalamic reticular nuclei, dorsal raphe nuclei, pedunculopontine, and laterodorsal tegmental nuclei. Co-localization between Scn1a immunoreactivity and critical cell types within these regions was also observed. EEG analysis under baseline conditions revealed increased wakefulness and reduced nonrapid eye movement (NREM) and rapid eye movement (REM) sleep amounts during the dark phase in the RH mutants, suggesting a sleep deficit. Nevertheless, the mutants exhibited levels of NREM and REM sleep that were generally similar to wild-type littermates during the recovery period following 6 h of sleep deprivation. Significance These results establish a direct role for SCN1A in the regulation of sleep and suggest that patients with SCN1A mutations may experience chronic alterations in sleep, potentially leading to negative outcomes over time. in addition, the expression of Scn1a in specific cell types/brain regions that are known to play critical roles in seizure generation and sleep now provides a mechanistic basis for the clinical features (seizures and sleep abnormalities) associated with human SCN1A mutations.
Palavra-chave Sleep
Epilepsy
Scn1a
Sodium channel
Sleep deprivation
Idioma Inglês
Financiador National Institutes of Health (NIH)
Associacao Fundo de Incentivo a Psicofarmacologia (AFIP)
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
National Institute of Neurological Disorders and Stroke (NINDS)
Número do financiamento National Institutes of Health (NIH): NS072221
National Institutes of Health (NIH): NS060659
National Institutes of Health (NIH): F31NS074717
FAPESP: 07/50534-0
FAPESP: 98/14303-3
National Institute of Neurological Disorders and Stroke (NINDS): P30N5055077
Data de publicação 2013-04-01
Publicado em Epilepsia. Hoboken: Wiley-Blackwell, v. 54, n. 4, p. 625-634, 2013.
ISSN 0013-9580 (Sherpa/Romeo, fator de impacto)
Publicador Wiley-Blackwell
Extensão 625-634
Fonte http://dx.doi.org/10.1111/epi.12060
Direito de acesso Acesso aberto Open Access
Tipo Artigo
Web of Science WOS:000316965500011
Endereço permanente http://repositorio.unifesp.br/handle/11600/36118

Exibir registro completo




Arquivo

Arquivo Tamanho Formato Visualização

Não existem arquivos associados a este item.

Este item está nas seguintes coleções

Buscar


Navegar

Minha conta