Attenuated ectopic action potential firing in parvalbumin expressing interneurons in a mouse model of Dravet Syndrome

Abstract

Dravet syndrome is caused by heterozygous loss-of-function variants in SCN1A, which encodes the voltage-gated sodium channel Nav1.1. Our recent work suggests that a primary pathogenic mechanism of Dravet syndrome is impaired action potential propagation along axons of cortical parvalbumin-positive fast-spiking GABAergic interneurons (PVINs). Ectopic action potentials (EAPs) are action potentials that initiate distal to the axon initial segment. We recently demonstrated that a large proportion of PVINs fire EAPs during periods of increased excitation. Although their function remains unknown, EAPs may play a role in 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 distal axonal excitability. We hypothesized that EAPs are attenuated in PVINs from Dravet syndrome (Scn1a+/-) mice due to dysfunction of the distal axon. We induced EAPs in PVINs in acute brain slices prepared from male and female wildtype (WT) and Scn1a+/- mice at P18-21 and P35-56, when we have previously identified axonal conduction deficits in Scn1a+/- PVINs. We elicited EAPs in 17/22 (77%) of WT PVINs, including 6 (22%) that exhibited barrages of EAPs. In contrast, Scn1a+/- PVINs never fired barrages (0%), and only 8/23 (34%) exhibited even single EAPs. This finding adds to the body of evidence supporting impaired action potential propagation in Dravet syndrome PVINs, and is the first evidence of impaired EAP firing in a disease model, suggesting that dysregulation of EAPs could be involved in the pathophysiology of human disease.