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- W4387470639 abstract "Dravet syndrome is an intractable developmental and epileptic encephalopathy caused by de novo variants in SCN1A resulting in haploinsufficiency of the voltage-gated sodium channel NaV1.1. We showed previously that administration of the antisense oligonucleotide STK-001, also called ASO-22, generated using Targeted Augmentation of Nuclear Gene Output technology to prevent inclusion of the nonsense-mediated decay or poison exon 20N in human SCN1A, increased productive Scn1a transcript and NaV1.1 expression and reduced the incidence of electrographic seizures and sudden unexpected death in epilepsy in a mouse model of Dravet syndrome. Here, we investigated the mechanism of action of ASO-84, a surrogate for ASO-22 that also targets splicing of SCN1A exon 20N, in Scn1a+/- Dravet syndrome mouse brain. Scn1a+/- Dravet syndrome and wildtype mice received a single intracerebroventricular injection of antisense oligonucleotide or vehicle at postnatal day 2. We examined the electrophysiological properties of cortical pyramidal neurons and parvalbumin-positive fast-spiking interneurons in brain slices at postnatal day 21-25 and measured sodium currents in parvalbumin-positive interneurons acutely dissociated from postnatal day 21-25 brain slices. We show that, in untreated Dravet syndrome mice, intrinsic cortical pyramidal neuron excitability was unchanged while cortical parvalbumin-positive interneurons showed biphasic excitability with initial hyperexcitability followed by hypoexcitability and depolarization block. Dravet syndrome parvalbumin-positive interneuron sodium current density was decreased compared to wildtype. GABAergic signaling to cortical pyramidal neurons was reduced in Dravet syndrome mice, suggesting decreased GABA release from interneurons. ASO-84 treatment restored action potential firing, sodium current density, and GABAergic signaling in Dravet syndrome parvalbumin-positive interneurons. Our work suggests that interneuron excitability is selectively affected by ASO-84. This new work provides critical insights into the mechanism of action of this antisense oligonucleotide and supports the potential of antisense oligonucleotide-mediated upregulation of NaV1.1 as a successful strategy to treat Dravet syndrome." @default.
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- W4387470639 date "2023-10-10" @default.
- W4387470639 modified "2023-10-11" @default.
- W4387470639 title "ASO restores excitability, GABA signalling and sodium current density in a model of Dravet syndrome" @default.
- W4387470639 doi "https://doi.org/10.1093/brain/awad349" @default.
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