Administration of the NMDA receptor antagonist, Phencyclidine (PCP), is widely used as a model for schizophrenia. However, numerous molecular alterations following PCP exposure are still to be uncovered. Here, prefrontal cortices (PFCs) from rats exposed to a single acute injection of PCP (10mg/kg, sc.) were used to investigate long-term expression profile (8h, 24h, and 48h) of the neuronal activity marker, c-fos, and three schizophrenia-relevant genes, parvalbumin, Gad67, and Chrna7. Furthermore, histone methylation status was analyzed by native chromatin immunoprecipitation (NChIP), using antibodies directed against H3K4me3, H3K9me2, and H3K27me3. Bisulfite conversion of unmethylated cytosine residues was used for DNA methylation analysis of the Chrna7 promoter.
The results indicate differential expression effects and histone alterations of PCP exposure on the investigated genes. c-fos was markedly upregulated after 8h, in spite of decreased H3K4me3 association. After 24h it was significantly decreased even though both H3K4me3 and H3K27me3 associations were decreased. Parvalbumin expression did not deviate from baseline at any of the investigated time-points, yet at 8h it was associated with less H3K4me3 and more H3K27me3. The α7-subunit gene, Chrna7, was downregulated 8h post-injection, correlating with the decreased association with H3K4me3. Furthermore, a tendency towards increased promoter DNA methylation was observed 8h post-injection. Exposure to PCP had a delayed effect on Gad67 expression, as this gene was upregulated 24h after administration, yet at both 8h and 48h, baseline values were observed. The only histone mark of importance for Gad67 regulation was H3K9me3, which was significantly more associated with the gene 24h after PCP exposure. Reports from post-mortem studies of schizophrenia-affected brains, consistently find decreased parvalbumin and Gad67 expression, while no alterations are found in Chrna7 expression. These discrepancies underline the difficulties encountered when modelling a complex human disorder in rodents.