# Multiomic Analyses Reveal Brainstem Metabolic Changes in a Mouse Model of Dravet Syndrome

## TL;DR

This study finds metabolic changes in the brainstem of mice with Dravet Syndrome, which may contribute to sudden death in epilepsy.

## Contribution

The study identifies age-specific brainstem metabolic changes and altered protein kinases in a mouse model of Dravet Syndrome.

## Key findings

- Glycolytic and pentose phosphate pathway intermediates are elevated in the brainstem of DS mice at P20–30.
- Mitochondrial aconitate and glutathione levels increase in the brainstem of older DS mice (P40–P50).
- Altered genes and protein kinase pathways in the brainstem suggest metabolic dysfunction in Dravet Syndrome.

## Abstract

There are widespread metabolic changes in the brainstem of Scn1aA1783V/WT HET mice.

Metabolomic analyses reveal age-specific metabolic alterations in the brainstem of HET mice.

Several druggable protein kinases are altered in the brainstem of HET mice.

The findings of this study suggest a role of metabolic alterations in the brainstem as a plausible contributor to SUDEP pathogenesis

Dravet Syndrome (DS) is a severe genetic epileptic encephalopathy caused by mutations in the SCN1A gene that encodes the voltage-gated sodium channel (NaV1.1) subunit alpha. DS is characterized by intractable seizures, progressive developmental delay, cognitive impairment, and high mortality due to sudden unexpected death in epilepsy (SUDEP). SUDEP is mediated by respiratory dysfunction, but the exact molecular underpinnings are unclear. Though hippocampal metabolic alterations have been reported in DS mice, such changes in brain regions controlling breathing have not been studied. We used Scn1aA1783V/WT DS mice to study temporal alterations in the brain metabolome, including analysis of brainstem and forebrain regions. Glycolytic and pentose phosphate pathway intermediates were significantly elevated in the brainstem of DS mice during the period of enhanced susceptibility to mortality (post-natal days P20–30). In older P40–P50 mice, mitochondrial aconitate and the antioxidant glutathione were significantly elevated in the brainstem. Single-nuclei RNA sequencing (snRNA seq) and proteomic analyses revealed alterations in genes associated with neurotransmission, cellular respiration, and protein translation, as well as reorganization of protein kinase-mediated pathways that are specific to the brainstem. These findings suggest that there are widespread metabolic changes in the brainstem of DS mice.