Expression changes in mouse brains following nicotine-induced seizures: the modulation of transcription factor networks.
Nicotine, acting through the neuronal nicotinic acetylcholine receptors (nAChRs), can induce seizures in mice. We aimed to study brain transcriptional response to seizure and to identify genes whose expression is altered after nicotine-induced seizures. Whole brains of untreated mice were compared with brains 1 h after seizure activity, using Affymetrix U74Av2 microarrays. Experimental groups included wild-type mice and both nicotine-induced seizure-sensitive and -resistant nAChR mutant mice. Each genotype group received different nicotine doses to generate seizures. This approach allowed the identification of significantly changed genes whose expression was dependent on seizure activity, nicotine administration, or both but not on the type of nAChR subunit mutation or the amount of nicotine injected. Significant expression changes were detected in 62 genes (P < 0.05, false discovery rate correction). Among them, gene ontology functional annotation analysis determined that the most significantly overrepresented categories were of genes encoding MAP kinase phosphatases, regulators of transcription and nucleosome assembly proteins. In silico bioinformatic analysis of the promoter regions of the 62 changed genes detected significant enrichments of 16 transcription regulatory elements (TREs), creating a network of transcriptional regulatory responses to seizures. The TREs for activating transcription factor and serum response factor were most significantly enriched, supporting their association with seizure activity. Our data suggest that nicotine-induced seizure in mice is a useful model to study seizure activity and its global brain transcriptional response. The differentially expressed genes detected here can help us to understand the molecular mechanisms underlying seizures in animal models and may also serve as candidate genes to study epilepsy in humans.
Kedmi
Merav
M
Genetic Institute, Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Orr-Urtreger
Avi
A
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D053263:Gene Regulatory Networks / Q000187:drug effects; D005838:Genotype; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics; D009538:Nicotine / Q000633:toxicity*; D020411:Oligonucleotide Array Sequence Analysis; D011978:Receptors, Nicotinic / Q000235:genetics; D012640:Seizures / Q000139:chemically induced* / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
C486720:Chrnb4 protein, mouse; D009419:Nerve Tissue Proteins; D011978:Receptors, Nicotinic; D014157:Transcription Factors; D009538:Nicotine