Expression changes in mouse brains following nicotine-induced seizures: the modulation of transcription factor networks

Abstract

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.

Tnfα, Cox2 and AdipoQ adipokine gene expression levels are modulated in murine adipose tissues by both nicotine and nACh receptors containing the β2 subunit

“…Amplified products and their sizes were verified by gel electrophoresis and confirmed by sequencing using BigDye Terminator v1.1 on an ABI PRISM 310 Genetic Analyzer (Applied Biosystems, Foster City, CA, USA). The expression of each gene was normalized using Hprt1 expression levels, and the quantification procedure was performed as previously described [38,39]. A standard curve was generated based on the calculation of the copy number for each gene.…”

Recent advances in gene manipulation and nicotinic acetylcholine receptor biology

“…The nicotine-induced seizures are accompanied by high-amplitude rhythmic discharges in EEG recordings [81]. Interestingly, nicotine-induced seizures affect gene expression differently in wild-type and α7L250T knock-in mice [82]. In wild-type mice, nicotine-induced seizures altered the expression of 559 genes, whereas in α7L250T mice 995 differentially expressed transcripts were found after nicotine treatment.…”

Epilepsy and nicotine: Clinical observations and a review of literature

“…Взаимодействуя с nAChRs префронтальной коры и лимбических систем, он вмешивается в метаболизм и модифицирует активность серотонин-, допамин-и адренергической трансмиссии, регуляцию опиатных систем, глютамата и глютаматных рецепторов, ингибиторов моноаминоксидазы. Соответственно, показана роль патологии nAChRs в патогенезе шизофрении, депрессии, синдрома дефицита внимания и гиперактивности, синдрома Туретта [15][16][17][18][19], эксперимен-тальных и клинических форм эпилепсии [20][21][22][23][24][25][26][27][28]. Роль nAChRs в патогенезе нервных и психических расстройств определяется тем, что они являются активными регуляторами Na+-зависимой возбуждающей нейротрансмиссии [15,16,27,29].…”

“…В основе ряда форм эпилепсии лежит генетически детерминированная дисфункция натриевых каналов [20,24,25,32,33]. У мышей обнаружены мутантные гены, изменяющие экспрессию nAChRs, что приводит к появлению у их носителей эпилептических припадков, провоцируемых никотином [24,34].…”

“…В основе ряда форм эпилепсии лежит генетически детерминированная дисфункция натриевых каналов [20,24,25,32,33]. У мышей обнаружены мутантные гены, изменяющие экспрессию nAChRs, что приводит к появлению у их носителей эпилептических припадков, провоцируемых никотином [24,34]. В клинических и экспериментальных исследованиях показано, что никотин может провоцировать эпилептические припадки и осложнение течения эпилепсии [29,35].…”