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. 2023 Oct 10;147(4):1231–1246. doi: 10.1093/brain/awad349

Figure 1.

Figure 1

A single intracerebroventricular dose of ASO-84 at P2 reduces SUDEP in Scn1a+/− mice, increases Scn1a mRNA and Nav1.1 protein in wild-type and Scn1a+/− mouse brains, and increases Scn1b expression in Scn1a+/− somatosensory cortex. (A) A single intracerebroventricular (ICV) dose of ASO-84 at P2 significantly improved survival of Scn1a+/− mice (solid blue) compared to PBS-treated Scn1a+/− mice (solid purple) through P90 (**P = 0.0088). Dashed purple: PBS-treated wild-type (WT) mice. Dashed blue: ASO-84-treated wild-type mice. Kaplan-Meier (Wilcoxon) analysis. (B) A single dose of ASO-84 at P2 (blue bars) significantly increased Scn1a mRNA abundance in P90 wild-type and Scn1a+/− mouse brains compared to PBS treatment (purple bars). **P < 0.0005; ****P < 0.0001. Data are presented as mean ± standard deviation (SD). Each data-point represents an independent sample from one animal. Unpaired Student’s t-tests were used to compare each ASO-treated genotype to its PBS control set to 1. (C) A single dose of ASO-84 at P2 (blue bars) significantly increased Nav1.1 protein in P90 wild-type and Scn1a+/− mouse brains compared to PBS treatment (purple bars). ****P < 0.0001; ns = no significant change. Data are presented as mean ± SD. Each data-point represents an independent sample from one animal. Two-way ANOVA followed by Tukey’s multiple comparisons test was used for comparison of means between independent groups. (D) A separate group of untreated animals showed a trending decrease in Scn1b mRNA expression in Scn1a+/− somatosensory cortex compared to wild-type mice (black bars, #P = 0.059). A single dose of ASO-84 at P2 (blue bars) significantly increased Scn1b mRNA in P17–18 Scn1a+/− mouse somatosensory cortex compared to untreated (black bars) Scn1a+/− cortex. The level of Scn1b mRNA expression in ASO-84-treated Scn1a+/− cortex was not significantly different from the level measured in untreated wild-type cortex. Each data-point represents an independent sample from one animal. Untreated WT: n = 9, ASO-84-treated WT: P = 7, untreated Scn1a+/−: n = 13, ASO-84-treated Scn1a+/−: n = 7. *P < 0.05; ns = no significant change (one-way ANOVA followed by Tukey’s multiple comparisons test). Data are presented as mean ± SD, with n equal to the number of independent samples from individual animals. SUDEP = sudden unexpected death in epilepsy.