Astrocyte‐Associated ABCA1/APOE Responses Accompany Hippocampal Lipid Remodeling and Ectopic Neuronal Accumulation During Epileptogenesis

Temporal lobe epilepsy (TLE) is characterized by progressive hippocampal remodeling, including reactive astrogliosis and aberrant neuronal positioning. Although lipid disturbances are implicated in epileptogenesis, how astrocyte-associated lipid responses relate to hippocampal remodeling remains poorly understood. Here, human TLE and kainic acid (KA)-treated mouse transcriptomic datasets identified ATP-binding cassette transporter A1 (ABCA1)/Abca1 as a nominal astrocyte-associated candidate, while KA- and pilocarpine-induced status epilepticus (SE) elicited astrocyte-associated ABCA1/apolipoprotein E (APOE) responses. Ectopic granule cells and immature neurons accumulated in the hilus and were spatially associated with ABCA1-positive cells, including astrocytic profiles; perilipin 2 (PLIN2)-positive puncta were nearby. Pretreatment with the retinoid X receptor (RXR) agonist bexarotene increased hippocampal ABCA1 expression, delayed severe KA-induced behavioral seizure onset, and was associated with fewer chronic spontaneous seizures and reduced ectopic neuronal accumulation. Post-SE bexarotene administration was associated with lower seizure frequency, ectopic neuronal accumulation, and astrocytic marker-positive cell densities. Multi-omic profiling identified bexarotene-associated metabolic and lipidomic changes; transmission electron microscopy (TEM) showed a smaller mean hilar neuronal lipid-droplet area per image, and protein analyses identified early changes in p38 and extracellular signal-regulated kinase 1/2 (Erk1/2) phosphorylation. Together, these findings warrant further investigation of astrocyte-associated lipid pathways as potential therapeutic targets in epilepsy-associated hippocampal remodeling.