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 NaV1.1, lead to a spectrum of neurological disease, including Dravet syndrome. NaV1.1 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 NaV1.6 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 NaV1.2 or NaV1.3. 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.