Abstract
Epilepsy is a widespread neurological disease characterized by abnormal neuronal activity resulting in recurrent seizures. There is mounting evidence that a circadian system disruption, involving clock genes and their downstream transcriptional regulators, is associated with epilepsy. In this study, we characterized the hippocampal expression of clock genes and PAR bZIP transcription factors (TFs) in a mouse model of temporal lobe epilepsy induced by intrahippocampal injection of kainic acid (KA). The expression of PAR bZIP TFs was significantly altered following KA injection as well as in other rodent models of acquired epilepsy. Although the PAR bZIP TFs are regulated by proinflammatory cytokines in peripheral tissues, we discovered that the regulation of their expression is inflammation-independent in hippocampal tissue and rather mediated by clock genes and hyperexcitability. Furthermore, we report that hepatic leukemia factor (Hlf), a member of PAR bZIP TFs family, is invariably downregulated in animal models of acquired epilepsy, regulates neuronal activity in vitro and its overexpression in dentate gyrus neurons in vivo leads to altered expression of genes associated with seizures and epilepsy. Overall, our study provides further evidence of PAR bZIP TFs involvement in epileptogenesis and points to Hlf as the key player.
Highlights
Epilepsy is a chronic brain disease characterized by the occurrence of recurrent seizures, which are the result of an excessive electrical discharge or hypersynchronization of a group of neurons in distinct areas of the brain
Decreased expression of clock genes as well as PAR bZIP transcription factors (TFs) was observed in NIH-3T3 cells or human synovial fibroblasts exposed to tumor necrosis factor α (TNF-α) or interleukin 1-β (IL-1β), and in the liver of mice injected with TNF-α or with CD40 agonistic antibodies[15,16,17,18]
We evaluated the hippocampal expression of core clock genes and PAR bZIP TFs at different stages during epileptogenesis by injecting kainic acid (KA) into the right dorsal hippocampus, a well-established model of TLE35
Summary
Epilepsy is a chronic brain disease characterized by the occurrence of recurrent seizures, which are the result of an excessive electrical discharge or hypersynchronization of a group of neurons in distinct areas of the brain. Core clock components interact with the expression of the proline and acidic amino acid-rich basic leucine zipper (PAR bZIP) transcription factors (TFs). This family is composed of three activators, DBP (albumin D-site-binding protein), HLF (hepatic leukemia factor), TEF (thyrotrophic embryonic factor) and one suppressor of transcription E4 Promoter-Binding Protein 4 (E4BP4), known as NFIL37–10. The triple knockout mouse deficient for the main three PAR bZIP transcription factors (Hlf, Dbp and Tef) developed generalized spontaneous seizures[12]. Our objective was to characterize the hippocampal expression of clock genes and PAR bZIP TFs in a kainic acid (KA) model of TLE and to dissect the interaction between them and neuroinflammation. We demonstrated that Hlf over-expression in primary hippocampal neurons leads to altered neuronal excitability in vitro and differential expression of genes involved in neuronal excitability, seizures and epilepsy in vivo
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
