Abstracts

Rationale: Dravet syndrome is caused by heterozygous loss-of-function variants in SCN1A, which encodes the voltage-gated sodium channel subunit Nav1.1. Recent work from our lab suggests that a primary pathogenic mechanism of Dravet syndrome is impaired action potential propagation along axons of parvalbumin-positive fast-spiking GABAergic interneurons (PVINs) in cerebral cortex. Ectopic action potentials (EAPs; also known as retro-axonal spikes) are action potentials that initiate distal to the axon initial segment. Although the function of EAPs remains unknown, they may play a role in both amplifying (when occurring in excitatory cells) and/or preventing seizures (when occurring in interneurons). Regardless of function, their generation in distal axons suggests that EAP frequency could be a useful proxy for axonal excitability. We hypothesized that EAPs would be attenuated in PVINs from Dravet syndrome mice due to dysfunction of the distal axon.

Methods: We induced retro-axonal spiking in PVINs from wildtype (WT) and Dravet syndrome (Scn1a^+/-) mice at P18-21 and P35-56, time points at which we previously identified axonal conduction deficits in Dravet syndrome PVINs.

Results: We elicited EAPs in 73% of WT PVINs (N = 8 mice, n = 15 cells), including 47% that exhibited retro-axonal barrages. In contrast, Dravet syndrome PVINs never fired barrages, and only 29% exhibited even single EAPs (N = 11, n = 24).

Conclusions: This finding adds to the body of evidence supporting impaired action potential propagation in Dravet syndrome PVINs, and is the first evidence that impaired ectopic action potentials could be involved in the pathophysiology of human disease.


Funding: NIH NINDS R01 NS110869 to E.M.G.
Dravet Syndrome Foundation Postdoctoral Fellowship to S.F.H.
Dravet Syndrome Foundation Research Grant to B.T.