The astrocyte Fabp7 gene regulates diurnal seizure threshold and activity-dependent gene expression in mice

Abstract

Epileptic seizures are often influenced by time-of-day and changes in vigilance state, yet the molecular and cellular mechanisms underpinning these associations remain poorly understood. Astrocytes, a pivotal type of glial cell, play a critical role in modulating neuronal excitability and circadian rhythms, and they express Fatty Acid Binding Protein 7 (Fabp7), a molecule vital for sleep regulation, lipid signaling, and gene transcription. This study investigates the role of Fabp7 in determining time-of-day dependent seizure susceptibility. We assessed electroshock seizure thresholds in male C57/BL6N wild-type (WT) and Fabp7 knockout (KO) mice. Results demonstrated that, compared to WT mice, Fabp7 KO mice displayed significantly elevated general and maximal electroshock seizure thresholds (GEST and MEST) during the dark phase, but not during the light phase. To explore the impact of Fabp7 on activity-dependent gene expression during seizures, we conducted RNA sequencing (RNA-seq) on cortical and hippocampal tissues from WT and Fabp7 KO mice following MEST and SHAM procedures during the dark period. While immediate early genes (IEGs) showed considerable differential expression between WT-MEST and WT-SHAM, this expression was absent in Fabp7 KO-MEST compared to Fabp7 KO-SHAM. Gene ontology analyses revealed significant overlaps between the WT-MEST:WT-SHAM and Fabp7 KO-SHAM:WT-SHAM comparisons, indicating that the basal mRNA expression profiles in Fabp7 KO brains resemble those of WT brains in a post-ictal state. Collectively, these findings suggest that Fabp7 is a key regulator of time-of-day dependent neural excitability and that astrocyte-mediated signaling pathways involving Fabp7 interact with neuronal activity to influence gene expression in response to seizures. Significance StatementChanges in sleep/wake state and/or circadian time-of-day are thought to influence neural excitability, which may confer seizure susceptibility. Here we describe a role for astrocytic Fabp7 in regulating nocturnal seizure threshold and gene expression associated with differences in seizure susceptibility, introducing an astrocyte factor that may represent a novel antiepileptic target for drug development.