Expression Profiling after Prolonged Experimental Febrile Seizures in Mice Suggests Structural Remodeling in the Hippocampus.

Bart C Jongbloets,Frank C P Holstege,Anne A Kan,Onno Van Nieuwenhuizen,Marina De Wit,Inge G Wolterink-Donselaar,Anneke H O Olde Engberink,Marian J A Groot Koerkamp,Pierre N E De Graan,Koen L I Van Gassen,Gilles Van Luijtelaar

doi:10.1371/journal.pone.0145247

Abstract

Febrile seizures are the most prevalent type of seizures among children up to 5 years of age (2–4% of Western-European children). Complex febrile seizures are associated with an increased risk to develop temporal lobe epilepsy. To investigate short- and long-term effects of experimental febrile seizures (eFS), we induced eFS in highly febrile convulsion-susceptible C57BL/6J mice at post-natal day 10 by exposure to hyperthermia (HT) and compared them to normotherm-exposed (NT) mice. We detected structural re-organization in the hippocampus 14 days after eFS. To identify molecular candidates, which entrain this structural re-organization, we investigated temporal changes in mRNA expression profiles eFS 1 hour to 56 days after eFS. We identified 931 regulated genes and profiled several candidates using in situ hybridization and histology at 3 and 14 days after eFS. This is the first study to report genome-wide transcriptome analysis after eFS in mice. We identify temporal regulation of multiple processes, such as stress-, immune- and inflammatory responses, glia activation, glutamate-glutamine cycle and myelination. Identification of the short- and long-term changes after eFS is important to elucidate the mechanisms contributing to epileptogenesis.

Highlights

Febrile seizures are the most prevalent type of seizures among children up to 5 years of age (2– 4% of Western-European children) [1]
To explore the hypothesis that hyperthermia-induced experimental febrile seizures (eFS) result in structural reorganization of the hippocampus, we compared neurofilament (NF, medium polypeptide) staining in hyperthermia-exposed mice (HT, n = 10) to normothermia-exposed control littermates (NT, n = 10) (Fig 1)
To investigate which molecular pathways underlie the structural reorganization after eFS, we compared hippocampal mRNA content from HT and NT mice by microarray hybridization

Summary

Introduction

Febrile seizures are the most prevalent type of seizures among children up to 5 years of age (2– 4% of Western-European children) [1]. Simple febrile seizures are generally benign, complex and especially prolonged febrile seizures, lasting longer than 10 minutes with recurring episodes, are thought to contribute to the development of epilepsy (epileptogenesis). Retrospective studies amongst temporal lobe epilepsy (TLE) patients show a higher incidence of complex or prolonged febrile seizures during childhood compared to other types of epilepsy, and have been suggested to be a precipitating or aggravating factor in the development of TLE [2,3,4,5]. Prolonged febrile seizures together with risk factors such as a family history of epilepsy, age of onset and underlying neurological abnormality, increase the risk of epilepsy later in life [8,9]. Animal models are highly suitable to study the relation between febrile seizures and epilepsy, and provide opportunity to monitor the underlying process of epileptogenesis

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Discussion

Conclusion