Developmentally regulated impairment of parvalbumin interneuron synaptic transmission in an experimental model of Dravet syndrome.
Cell Rep
; 38(13): 110580, 2022 03 29.
Article
em En
| MEDLINE
| ID: mdl-35354025
ABSTRACT
Dravet syndrome is a neurodevelopmental disorder characterized by epilepsy, intellectual disability, and sudden death due to pathogenic variants in SCN1A with loss of function of the sodium channel subunit Nav1.1. Nav1.1-expressing parvalbumin GABAergic interneurons (PV-INs) from young Scn1a+/- mice show impaired action potential generation. An approach assessing PV-IN function in the same mice at two time points shows impaired spike generation in all Scn1a+/- mice at postnatal days (P) 16-21, whether deceased prior or surviving to P35, with normalization by P35 in surviving mice. However, PV-IN synaptic transmission is dysfunctional in young Scn1a+/- mice that did not survive and in Scn1a+/- mice ≥ P35. Modeling confirms that PV-IN axonal propagation is more sensitive to decreased sodium conductance than spike generation. These results demonstrate dynamic dysfunction in Dravet syndrome combined abnormalities of PV-IN spike generation and propagation drives early disease severity, while ongoing dysfunction of synaptic transmission contributes to chronic pathology.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Parvalbuminas
/
Epilepsias Mioclônicas
Limite:
Animals
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article