Epigenetics in Schizophrenia: Study of Epigenetic Regulation of Schizophrenia-relevant Genes in Phencyclidine Treated Rats
Author
Donovan, Lene Lundgaard
Term
4. term
Publication year
2014
Submitted on
2014-05-28
Pages
59
Abstract
Fencyclidin (PCP) er en NMDA-receptorantagonist, der ofte bruges til at efterligne visse træk ved skizofreni i dyremodeller. I denne undersøgelse så vi på, hvordan en enkelt, akut PCP-injektion (10 mg/kg, subkutant) påvirker genaktivitet over tid i rotters præfrontale cortex. Vi målte udtrykket af aktivitetsmarkøren c‑fos samt tre skizofrenirelaterede gener: parvalbumin, Gad67 og Chrna7, 8, 24 og 48 timer efter injektionen. Samtidig undersøgte vi epigenetiske ændringer, dvs. kemiske mærker, der kan påvirke om gener er tændt eller slukket. Vi analyserede histonmethylation med NChIP for H3K4me3, H3K9me2 og H3K27me3, og vi målte DNA‑methylation i Chrna7‑promotoren ved bisulfitkonvertering. Resultaterne viser gen‑ og tidsafhængige virkninger af PCP. c‑fos var tydeligt opreguleret efter 8 timer, selv om dets tilknytning til H3K4me3 var reduceret. Efter 24 timer var c‑fos nedreguleret, samtidig med at både H3K4me3‑ og H3K27me3‑tilknytning var lavere. Parvalbumin‑ekspressionen lå omkring udgangspunktet på alle tidspunkter, men efter 8 timer var den forbundet med mindre H3K4me3 og mere H3K27me3. Chrna7 var nedreguleret efter 8 timer og havde samtidig mindre H3K4me3‑tilknytning; desuden sås en tendens til øget DNA‑methylation i promotoren på dette tidspunkt. Gad67 viste en forsinket respons med opregulering efter 24 timer, men niveauer ved basislinjen efter 8 og 48 timer; her fremstod en H3K9‑methylationsmarkør som særligt associeret med genet 24 timer efter PCP. Samlet peger data på, at PCP udløser forskellige og tidsafhængige mønstre i genudtryk og kromatinmærker. Sammenlignet med postmortem‑fund ved skizofreni—typisk lavere parvalbumin og Gad67 samt uændret Chrna7—viser uoverensstemmelserne, hvor vanskeligt det er at modellere en kompleks menneskelig lidelse i gnavere.
Phencyclidine (PCP), an NMDA receptor antagonist, is widely used to mimic certain features of schizophrenia in animal models. In this study, we examined how a single acute PCP injection (10 mg/kg, subcutaneous) alters gene activity over time in the rat prefrontal cortex. We measured the expression of the neuronal activity marker c‑fos and three schizophrenia‑relevant genes—parvalbumin, Gad67, and Chrna7—at 8, 24, and 48 hours after injection. We also assessed epigenetic changes, meaning chemical tags that can influence whether genes are switched on or off. Histone methylation was analyzed by NChIP for H3K4me3, H3K9me2, and H3K27me3, and DNA methylation at the Chrna7 promoter was measured by bisulfite conversion. The results show gene‑specific, time‑dependent effects of PCP. c‑fos was strongly upregulated at 8 hours despite reduced association with H3K4me3. By 24 hours, c‑fos was downregulated even though both H3K4me3 and H3K27me3 associations were decreased. Parvalbumin expression stayed near baseline at all time points, but at 8 hours it was linked to less H3K4me3 and more H3K27me3. Chrna7 was downregulated at 8 hours alongside reduced H3K4me3 association; a trend toward increased promoter DNA methylation was also observed at this time. Gad67 showed a delayed response with upregulation at 24 hours and baseline levels at 8 and 48 hours; here, an H3K9 methylation mark stood out as more strongly associated with the gene at 24 hours. Overall, PCP triggers distinct, time‑dependent patterns in gene expression and chromatin marks. Compared with post‑mortem findings in schizophrenia—typically reduced parvalbumin and Gad67 and unchanged Chrna7—these discrepancies highlight the challenges of modeling a complex human disorder in rodents.
[This abstract was generated with the help of AI]
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