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Brainstem metabolic changes in a mouse model of Dravet Syndrome

ABSTRACT: 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). Post-ictal apnea that precedes asystole has been observed to lead to SUDEP; however, the exact molecular underpinnings are unclear. Seizure-induced hippocampal metabolic alterations have been reported in DS mice. Whether such alterations occur in the brainstem, a master regulator of autonomic functions, thereby influencing morbidity, mortality/SUDEP, and seizure outcomes is unknown. We used Scn1aA1783V/WT DS mice and showed that there are temporal alterations in the brainstem metabolome which are distinct in comparison to the forebrain metabolome. 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 day P20-30). Post P20-30, mitochondrial aconitate, and the antioxidant glutathione were significantly elevated. Single nuclei RNA sequencing (snRNA seq), and proteomic analyses revealed alterations in genes associated with neurotransmission, cellular respiration, protein translation, as well as systematic rewiring of protein kinase-mediated pathways that were specific to the brainstem. These findings suggest that there are widespread metabolic changes in the brainstem of DS mice that are associated with alterations in druggable molecular pathways.

ORGANISM(S): Mus musculus

PROVIDER: GSE301399 | GEO | 2025/12/30

REPOSITORIES: GEO

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Project description:Neuropsychiatric consequences of poorly controlled seizures that begin in childhood can be devastating. School failure or behavioral difficulty in a child with epilepsy is common and can become the focus of concern for families. Current antiepileptic drugs compound problems with their CNS side effects; effective therapy is currently limited as little is known about the cellular and molecular changes caused by seizures in the developing brain. This study will investigate transcriptional regulation induced by early-life seizures and explore alternative nonpharmacological therapeutic strategies in reversing damages of early-life seizures. We will study the therapeutic efficacy of environmental enrichment in reducing seizure-induced neuronal injury and in modifying gene expression alterations. We will explore molecular mechanisms underlying the beneficial effects of enriched environment and examine how different genes act in concert to influence the outcome of seizure-induced damage. To test the effect of environmental enrichment in modifying KA seizure-induced alterations in gene expression. We hypothesize that environmental enrichment enhances plastic, homeostatic response of immature brain to excessive, dysregulating seizure activity and protect against maladaptive response of developing animals to seizures. After inducing seizures by systemic injection of KA (8 mg/kg) or PBS injections (control) at P20, we will randomly assign P21 male Long Evans rats to 4 groups: enrichment housing (control-enriched; SE-enriched) or to standard vivarium cages (control; SE). Sixteen animals (8 control-enriched; 8 SE-enriched) will be housed as a group in a plastic rectangular cage measuring 115cm x 80 cm containing a running wheel, tunnels, rubber balls, a maze, a mirror, and a clock with a cyclist pendulum. Control and KA will be housed individually in a standard cage. Four litters will be used for each run of experiment and the experiment will be repeated once to obtain 16 animals per group. At P30, 240 h after KA or PBS, animals will be deeply anesthetized with isoflurane, decapitated for total RNA preparation (half brain for each, n = 12 per group). Total RNA will be isolated from each hippocampus individually, and equal amounts of RNA from 4 hippocampi will be pooled for each Genechip. Three independent hybridizations will be performed per condition (total of 12 Genechip Rat Expression Set 230).

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Brainstem metabolic changes in a mouse model of Dravet Syndrome

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