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.
Original language | English |
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Article number | 110580 |
Journal | Cell Reports |
Volume | 38 |
Issue number | 13 |
DOIs | |
Publication status | Published - 29 Mar 2022 |
Externally published | Yes |
Keywords
- CP: Neuroscience
- Dravet syndrome
- GABAergic interneurons
- Nav1.1
- SCN1A
- epilepsy