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

Cilla Zhou; Vaishali Satpute; Ka Lai Yip; Lyndsey L Anderson; Nicole Hawkins; Jennifer Kearney; Jonathon C Arnold

doi:10.1016/j.prostaglandins.2024.106836

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

Prostaglandins Other Lipid Mediat. 2024 Apr 9:172:106836. doi: 10.1016/j.prostaglandins.2024.106836. Online ahead of print.

Authors

Cilla Zhou¹, Vaishali Satpute², Ka Lai Yip², Lyndsey L Anderson², Nicole Hawkins³, Jennifer Kearney³, Jonathon C Arnold⁴

Affiliations

¹ Lambert Initiative for Cannabinoid Therapeutics, The University of Sydney, Sydney, NSW 2050, Australia; Discipline of Pharmacology, School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia; Brain and Mind Centre, The University of Sydney, Sydney, NSW 2050, Australia; Department of Pharmacology, Feinberg School of Medicine, Northwestern University, IL 60611, USA.
² Lambert Initiative for Cannabinoid Therapeutics, The University of Sydney, Sydney, NSW 2050, Australia; Discipline of Pharmacology, School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia; Brain and Mind Centre, The University of Sydney, Sydney, NSW 2050, Australia.
³ Department of Pharmacology, Feinberg School of Medicine, Northwestern University, IL 60611, USA.
⁴ Lambert Initiative for Cannabinoid Therapeutics, The University of Sydney, Sydney, NSW 2050, Australia; Discipline of Pharmacology, School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia; Brain and Mind Centre, The University of Sydney, Sydney, NSW 2050, Australia. Electronic address: jonathon.arnold@sydney.edu.au.

PMID: 38599513
DOI: 10.1016/j.prostaglandins.2024.106836

Abstract

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, PGE₂, PGD₂, 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.

Keywords: Dravet syndrome; Epilepsy; Microglia; Neuroinflammation; Prostaglandins; Seizures.