Abstract
Dravet syndrome (DS) is a neurodevelopmental disorder due to pathogenic variants in SCN1A encoding the Nav1.1 sodium channel subunit, characterized by treatment-resistant epilepsy, temperature-sensitive seizures, developmental delay/intellectual disability with features of autism spectrum disorder, and increased risk of sudden death. Convergent data suggest hippocampal dentate gyrus (DG) pathology in DS (Scn1a+/-) mice. We performed two-photon calcium imaging in brain slice to uncover a profound dysfunction of filtering of perforant path input by DG in young adult Scn1a+/- mice. This was not due to dysfunction of DG parvalbumin inhibitory interneurons (PV-INs), which were only mildly impaired at this timepoint; however, we identified enhanced excitatory input to granule cells, suggesting that circuit dysfunction is due to excessive excitation rather than impaired inhibition. We confirmed that both optogenetic stimulation of entorhinal cortex and selective chemogenetic inhibition of DG PV-INs lowered seizure threshold in vivo in young adult Scn1a+/- mice. Optogenetic activation of PV-INs, on the other hand, normalized evoked responses in granule cells in vitro. These results establish the corticohippocampal circuit as a key locus of pathology in Scn1a+/- mice and suggest that PV-INs retain powerful inhibitory function and may be harnessed as a potential therapeutic approach toward seizure modulation.
Highlights
Pathogenic variants in SCN1A, which encodes the voltage-gated sodium channel subunit Nav1.1, cause a spectrum of epilepsies including Dravet syndrome (DS) (Claes et al, 2001), the most common developmental and epileptic encephalopathy
In this study, we demonstrate a profound hyperexcitability of the corticohippocampal circuit in young adult Scn1a+/- mice that is not present at epilepsy onset using two-photon calcium imaging and cellular and synaptic physiology in an acute slice preparation
We found that bath-application of Hm1a to brain slices prepared from Scn1a+/- mice corrected the parvalbumin inhibitory interneurons (PV-INs) deficits apparent in response to large and prolonged current injections, whereas Hm1a had no impact on firing of PV-INs from wild-type mice, consistent with prior literature (Richards et al, 2018) (Figure 4A-D)
Summary
Pathogenic variants in SCN1A, which encodes the voltage-gated sodium channel subunit Nav1.1, cause a spectrum of epilepsies including Dravet syndrome (DS) (Claes et al, 2001), the most common developmental and epileptic encephalopathy. When expressed on a 50:50 129S6:C57BL/6J genetic background, these mice exhibit spontaneous seizures beginning at approximately post-natal day (P) 18, and high rates of sudden unexpected death in epilepsy (SUDEP) (Mistry et al, 2014). These mice exhibit temperature-sensitive seizures, akin to seizures triggered in the setting of fever or hyperthermia in human patients with DS, which represents a key experimental advantage of this mouse model as it readily facilitates study of inducible but naturalistic seizures in vivo (Tran et al, 2020)
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