Interneurons exhibit attenuated ectopic action potential firing in a severe neurodevelopmental disorder

Dravet syndrome (DS) is a severe neurodevelopmental disorder associated with treatment-resistant epilepsy and features of autism spectrum disorder due to loss of the voltage-gated sodium channel subunit Nav1.1. Recent work suggests that a pathogenic mechanism of DS is impaired action potential propagation along axons of cerebral cortex parvalbumin-positive fast-spiking GABAergic interneurons (PVINs). Here, we investigated another aspect of axonal physiology: action potentials generated in the distal axon, known as "ectopic" action potentials (EAPs). We hypothesized that EAP frequency could be a proxy for the excitability of the distal axon and that EAPs would be attenuated in neocortical layer 2/3 PVINs from DS mice due to axonal dysfunction. We identified reduced EAP generation in DS PVINs at both postnatal day (P)18-21 and P35-56 and a complete absence of barrage (repetitive EAP) firing. This is the first evidence of impaired EAP firing in a disease model.NEW & NOTEWORTHY Dravet syndrome (DS) is a severe form of epilepsy primarily caused by reduced excitability of inhibitory neurons. Our research identifies a new abnormality in DS mice: reduced ectopic action potentials (EAPs). We have previously shown that EAPs are engaged after increased excitability, manifesting in most parvalbumin-expressing interneurons (PVINs) as a high-frequency train of persistent action potentials. Our work represents the first evidence linking a deficiency in EAP generation-an underexplored intrinsic property-with any neuropathology.