A high seizure burden increases several prostaglandin species in the hippocampus of a Scn1a +/- mouse model of Dravet syndrome.

Dravet syndrome is an intractable epilepsy with a high seizure burden that is resistant to current anti-seizure medications. There is evidence that neuroinflammation plays a role in epilepsy and seizures, however few studies have specifically examined neuroinflammation in Dravet syndrome under conditions of a higher seizure burden. Here we used an established genetic mouse model of Dravet syndrome (Scn1a ^+/- mice), to examine whether a higher seizure burden impacts the number and morphology of microglia in the hippocampus. Moreover, we examined whether a high seizure burden influences classical inflammatory mediators in this brain region. Scn1a ^+/- mice with a high seizure burden induced by thermal priming displayed a localised reduction in microglial cell density in the granule cell layer and subgranular zone of the dentate gyrus, regions important to postnatal neurogenesis. However, microglial cell number and morphology remained unchanged in other hippocampal subfields. The high seizure burden in Scn1a ^+/- mice did not affect hippocampal mRNA expression of classical inflammatory mediators such as interleukin 1β and tumour necrosis factor α, but increased cyclooxygenase 2 (COX-2) expression. We then quantified hippocampal levels of prostanoids that arise from COX-2 mediated metabolism of fatty acids and found that Scn1a ^+/- mice with a high seizure burden displayed increased hippocampal concentrations of numerous prostaglandins, notably PGF _2α , PGE ₂ , PGD ₂ , and 6-K-PGF _1A , compared to Scn1a ^+/- mice with a low seizure burden. In conclusion, a high seizure burden increased hippocampal concentrations of various prostaglandin mediators in a mouse model of Dravet syndrome. Future studies could interrogate the prostaglandin pathways to further better understand their role in the pathophysiology of Dravet syndrome.
Competing Interests: Declaration of Competing Interest JCA is Deputy Academic Director of the Lambert Initiative for Cannabinoid Therapeutics, a philanthropically funded research program at the University of Sydney. He has served as an expert witness in various medicolegal cases involving cannabis and has received consulting fees from the World Health Organization (WHO), Medical Cannabis Industry Australia (MCIA) and Haleon (consumer healthcare subsidiary of Glaxo Smith-Kline). He reports research grants from the Australian National Health and Medical Research Council (NHMRC) and from Lambert Initiative for Cannabinoid Therapeutics. He is an inventor on patents WO2019227167 and WO2019071302 issued, which relate to cannabinoid therapeutics. JAK serves on the Scientific Advisory Boards of the Dravet Syndrome Foundation and FamilieSCN2A Foundation. She receives research funding from the National Institutes of Health (USA), Neurocrine Biosciences, and Praxis Precision Medicines. She reports consulting fees from PTC Therapeutics and royalty payments from Biogen, Emugen, Encoded Therapeutics, GlaxoSmithKline, GW Pharmaceuticals, Hoffamn-LaRoche, Noema Pharma, Novartis, Pfizer, Regel Therapeutics, Sangamo, Stoke Therapeutics, StrideBio, Tevard, U1 Bio, Xenon Pharmaceuticals. The other authors declare no conflict of interest.
(Copyright © 2024. Published by Elsevier Inc.)