Compensatory rearrangement of parvalbumin interneuron voltage‐gated sodium channel subunits in a mouse model of Dravet syndrome

Heterozygous loss‐of‐function variants in the gene SCN1A , which encodes the voltage‐gated sodium channel (VGSC) pore‐forming (α) subunit Na V 1.1, lead to a spectrum of neurological disease, including Dravet syndrome. Na V 1.1 is prominently expressed at the proximal portion of the axon initial segment (AIS) of fast‐spiking γ‐aminobutyric acidergic parvalbumin‐expressing inhibitory interneurons (PV+INs). In Dravet syndrome ( Scn1a +/− haploinsufficient) mice, action potential firing is impaired in PV+INs during postnatal development; however, in mature animals, PV+IN fast‐firing frequency has recovered. We used detailed immunohistochemistry and microscopy to probe the mechanism of this functional recovery, investigating potential upregulation of other brain‐expressed VGSC subunits at the PV+IN AIS. We found a specific upregulation of Na V 1.6 immunofluorescence at the AIS of PV+INs in adult (but not developing) Scn1a +/− mice compared to wild type, with no upregulation of other brain‐expressed subunits Na V 1.2 or Na V 1.3. These results demonstrate one mechanism through which epilepsy‐related gene variants reorganize the developing brain and enact endogenous changes that may be at least partially compensatory.