Excessive novelty-induced c-Fos expression and altered neurogenesis in the hippocampus of GluA1 knockout mice

a−Amino−3−hydroxy−5−methyl−4−isoxazolepropionic acid (AMPA) receptor GluA1 subunit−deficient (GluA1) / )) mice display noveltyinduced hyperactivity, cognitive and social defects and may model psychiatric disorders, such as schizophrenia and depression / mania. We used c−Fos expression in GluA1) / ) mice to identify brain regions responsible for novelty−induced hyperlocomotion. Exposure to a novel cage for 2 h significantly increased c−Fos expression in many brain regions in both wild−type and knockout mice. Interestingly, the clearest genotype effect was observed in the hippocampus and its main input region, the entorhinal cortex, where the novelty−induced c−Fos expression was more strongly enhanced in GluA1) / ) mice. Their novelty−induced hyperlocomotion partly depended on the activity of AMPA receptors, as it was diminished by the AMPA receptor antagonist 2,3−dioxo−6−nitro−1,2,3,4− tetrahydrobenzo[f]quinoxaline−7−sulphonamide (NBQX) and unaffected by the AMPA receptor potentiator 2,3−dihydro−1,4−benzodioxin− 6−yl−1−piperidinylmethanone (CX546). The hyperlocomotion of GluA1) / ) mice was normalised to the level of wild−type mice within 5−6 h, after which their locomotion followed normal circadian rhythm and was not affected by acute or chronic treatments with the selective serotonin reuptake inhibitor escitalopram. We propose that hippocampal dysfunction, as evidenced by the excessive c− Fos response to novelty, is the major contributor to novelty−induced hyperlocomotion in GluA1) / ) mice. Hippocampal dysfunction was also indicated by changes in proliferation and survival of adult−born dentate gyrus cells in the knockout mice. These results suggest focusing on the functions of hippocampal formation, such as novelty detection, when using the GluA1) / ) mouse line as a model for neuropsychiatric and cognitive disorder

DNA Methylation Regulates Cocaine-Induced Behavioral Sensitization in Mice

The behavioral sensitization produced by repeated cocaine treatment represents the neural adaptations underlying some of the features of addiction in humans. Cocaine administrations induce neural adaptations through regulation of gene expression. Several studies suggest that epigenetic modifications, including DNA methylation, are the critical regulators of gene expression in the adult central nervous system. DNA methylation is catalyzed by DNA methyltransferases (DNMTs) and consequent promoter region hypermethylation is associated with transcriptional silencing. In this study a potential role for DNA methylation in a cocaine-induced behavioral sensitization model in mice was explored. We report that acute cocaine treatment caused an upregulation of DNMT3A and DNMT3B gene expression in the nucleus accumbens (NAc). Using methylated DNA immunoprecipitation, DNA bisulfite modification, and chromatin immunoprecipitation assays, we observed that cocaine treatment resulted in DNA hypermethylation and increased binding of methyl CpG binding protein 2 (MeCP2) at the protein phosphatase-1 catalytic subunit (PP1c) promoter. These changes are associated with transcriptional downregulation of PP1c in NAc. In contrast, acute and repeated cocaine administrations induced hypomethylation and decreased binding of MeCP2 at the fosB promoter, and these are associated with transcriptional upregulation of fosB in NAc. We also found that pharmacological inhibition of DNMT by zebularine treatment decreased cocaine-induced DNA hypermethylation at the PP1c promoter and attenuated PP1c mRNA downregulation in NAc. Finally, zebularine and cocaine co-treatment delayed the development of cocaine-induced behavioral sensitization. Together, these results suggest that dynamic changes of DNA methylation may be an important gene regulation mechanism underlying cocaine-induced behavioral sensitization