title: Spatiotemporal differences in the c-fos pathway between C57BL/6J and DBA/2J mice following flurothyl-induced seizures: A dissociation of hippocampal Fos from seizure activity.
abstract: Significant differences in seizure characteristics between inbred mouse strains highlight the importance of genetic predisposition to epilepsy. Here, we examined the genetic differences between the seizure-resistant C57BL/6J (B6) mouse strain and the seizure-susceptible DBA/2J (D2) strain in the phospho-Erk and Fos pathways to examine seizure-induced neuronal activity to uncover potential mechanistic correlates to these disparate seizure responsivities. Expression of neural activity markers was examined following 1, 5, or 8 seizures, or after 8 seizures, a 28 day rest period, and a final flurothyl rechallenge. Two brain regions, the hippocampus and ventromedial nucleus of the hypothalamus (VMH), had significantly different Fos expression profiles following seizures. Fos expression was highly robust in B6 hippocampus following one seizure and remained elevated following multiple seizures. Conversely, there was an absence of Fos (and phospho-Erk) expression in D2 hippocampus following one generalized seizure that increased with multiple seizures. This lack of Fos expression occurred despite intracranial electroencephalographic recordings indicating that the D2 hippocampus propagated ictal discharge during the first flurothyl seizure suggesting a dissociation of seizure discharge from Fos and phospho-Erk expression. Global transcriptional analysis confirmed a dysregulation of the c-fos pathway in D2 mice following 1 seizure. Moreover, global analysis of RNA expression differences between B6 and D2 hippocampus revealed a unique pattern of transcripts that were co-regulated with Fos in D2 hippocampus following 1 seizure. These expression differences could, in part, account for D2's seizure susceptibility phenotype. Following 8 seizures, a 28 day rest period, and a final flurothyl rechallenge, ∼85% of B6 mice develop a more complex seizure phenotype consisting of a clonic-forebrain seizure that uninterruptedly progresses into a brainstem seizure. This seizure phenotype in B6 mice is highly correlated with bilateral Fos expression in the VMH and was not observed in D2 mice, which always express clonic-forebrain seizures upon flurothyl retest. Overall, these results illustrate specific differences in protein and RNA expression in different inbred strains following seizures that precede the reorganizational events that affect seizure susceptibility and changes in seizure semiology over time.
authors.affiliation: Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA.
authors.forename: Sridhar B
authors.initials: SB
authors.lastname: Kadiyala
authors.affiliation: Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA; Department of Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA.
authors.forename: Dominick
authors.initials: D
authors.lastname: Papandrea
authors.affiliation: Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA.
authors.forename: Karina
authors.initials: K
authors.lastname: Tuz
authors.affiliation: Department of Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA.
authors.forename: Tara M
authors.initials: TM
authors.lastname: Anderson
authors.affiliation: Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA.
authors.forename: Sachidhanand
authors.initials: S
authors.lastname: Jayakumar
authors.affiliation: Wadsworth Center, Albany, NY 12201, USA; Department of Biomedical Sciences, School of Public Health, SUNY Albany, Albany, NY 12201, USA.
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Herron
authors.affiliation: Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA; Department of Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA; Department of Neurology, Albany Medical College, Albany, NY 12208, USA. Electronic address: ferlanr@mail.amc.edu.
authors.forename: Russell J
authors.initials: RJ
authors.lastname: Ferland
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D004567:Electrodes, Implanted; D004569:Electroencephalography; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005481:Flurothyl; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D006624:Hippocampus / Q000503:physiopathology*; D007150:Immunohistochemistry; D008297:Male; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D012640:Seizures / Q000503:physiopathology*; D013045:Species Specificity
chemical_list: D016760:Proto-Oncogene Proteins c-fos; D005481:Flurothyl; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Epilepsy; Erk; Fos; Genomics; Hippocampus; Ventromedial nucleus of the hypothalamus