Abstracts

Rationale: Dravet syndrome (DS), a catastrophic pediatric epilepsy, is commonly caused by de novo (80%-95%) mutations in the voltage-gated sodium channel subunit α1 (SCN1A). DS is characterized by early-life febrile seizures with eventual progression to spontaneous pharmaco-resistant seizures, intellectual disability, psychomotor dysfunction, and a high rate of sudden unexpected death in epilepsy (SUDEP). Although the exact sequence of events that lead to SUDEP is unclear, post-ictal apnea that causes respiratory distress and precedes asystole has been recognized as an important pathomechanism. Given that the brainstem is a key regulator of respiration, cardiac function and arousal, repeated seizure spread to this brain region can place a huge energy demand that may exhaust metabolic resources and impair neurometabolic coupling. Previous studies in mouse and zebrafish models of DS highlighted significant changes to the metabolome suggesting an overall hypometabolic state (Miljanovic N et al., 2021; Kumar MG et al., 2016). However, whether such metabolic alterations occur in the brainstem and contribute to respiratory distress and subsequent SUDEP in DS mice have not been evaluated. So, we asked if there would be metabolic alterations in the brain stem of DS mice particularly during the critical period of enhanced susceptibility to SUDEP.

Methods: Dravet syndrome HET mice (Scn1a^A1783V/WT; Sox-Cre C57Bl/6J) (both male and female) exhibit a high mortality rate (~50% through P60). The greatest proportion of these deaths occur between P15 and P30, which suggests the presence of a critical period of SUDEP susceptibility in these animals. Brain and plasma samples were collected from age-matched WT and HET animals at P25 and submitted for metabolomic profiling (GC-MS platform; Metabolomics Core Facility; University of Utah).

Results: Metabolomic profiling of hindbrain samples from HET animals revealed a significant increase in glucose-6-phosphate (G6P) (p< 0.05 vs. WT), suggesting elevated functioning of several associated biochemical pathways including glycogenolysis. A significant increase in fructose-6-phosohate (F6P) and sedoheptulose-7-phosphate (p< 0.05 vs. WT) was detected which could suggest enhanced glucose catabolism plausibly via the glycolytic and pentose phosphate pathways. Increased levels (p< 0.05 vs. WT) of inosine, an adenosine metabolite, were also detected in hindbrain samples. Inosine, like adenosine has been shown to aid with seizure cessation possibly by interacting with adenosinergic receptors.