title: Chronic mild stress and antidepressant treatment alter 5-HT1A receptor expression by modifying DNA methylation of a conserved Sp4 site.
abstract: The serotonin 1A receptor (5-HT1A), a critical regulator of the brain serotonergic tone, is implicated in major depressive disorder (MDD) where it is often found to be dys-regulated. However, the extent to which stress and antidepressant treatment impact 5-HT1A expression in adults remains unclear. To address this issue, we subjected adult male BALB/c mice to unpredictable chronic mild stress (UCMS) to induce a depression-like phenotype that was reversed by chronic treatment with the antidepressant imipramine. In prefrontal cortex (PFC) and midbrain tissue, UCMS increased 5-HT1A RNA and protein levels, changes that are expected to decrease the brain serotonergic activity. The stress-induced increase in 5-HT1A expression was paralleled by a specific increase in DNA methylation of the conserved -681 CpG promoter site, located within a Sp1-like element. We show that the -681 CpG site is recognized and repressed by Sp4, the predominant neuronal Sp1-like factor and that Sp4-induced repression is attenuated by DNA methylation, despite a stress-induced increase in PFC Sp4 levels. These results indicate that adult life stress induces DNA methylation of a conserved promoter site, antagonizing Sp4 repression to increase 5-HT1A expression. Chronic imipramine treatment fully reversed the UCMS-induced increase in methylation of the -681 CpG site in the PFC but not midbrain of stressed animals and also increased 5-HT1A expression in the PFC of control animals. Incomplete reversal by imipramine of stress-induced changes in 5-HT1A methylation and expression indicates a persistence of stress vulnerability, and that sustained reversal of behavioral impairments may require additional pathways.
authors.affiliation: Ottawa Hospital Research Institute (Neuroscience), University of Ottawa, Ottawa, ON K1H 8M5, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
authors.forename: Brice
authors.initials: B
authors.lastname: Le François
authors.affiliation: Ottawa Hospital Research Institute (Neuroscience), University of Ottawa, Ottawa, ON K1H 8M5, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Soo
authors.affiliation: Ottawa Hospital Research Institute (Neuroscience), University of Ottawa, Ottawa, ON K1H 8M5, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Millar
authors.affiliation: Ottawa Hospital Research Institute (Neuroscience), University of Ottawa, Ottawa, ON K1H 8M5, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
authors.forename: Mireille
authors.initials: M
authors.lastname: Daigle
authors.affiliation: Inserm U 930, Université François Rabelais, 37200 Tours, France.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Le Guisquet
authors.affiliation: Inserm U 930, Université François Rabelais, 37200 Tours, France.
authors.forename: Samuel
authors.initials: S
authors.lastname: Leman
authors.affiliation: Inserm U 930, Université François Rabelais, 37200 Tours, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Minier
authors.affiliation: Inserm U 930, Université François Rabelais, 37200 Tours, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Belzung
authors.affiliation: Ottawa Hospital Research Institute (Neuroscience), University of Ottawa, Ottawa, ON K1H 8M5, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada. Electronic address: palbert@uottawa.ca.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Albert
mesh_terms: D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D002908:Chronic Disease; D017124:Conserved Sequence; D018899:CpG Islands; D019175:DNA Methylation / Q000187:drug effects* / Q000502:physiology; D003866:Depressive Disorder / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D065847:Dorsal Raphe Nucleus / Q000187:drug effects / Q000378:metabolism; D007099:Imipramine / Q000494:pharmacology; D008297:Male; D008807:Mice, Inbred BALB C; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics* / Q000378:metabolism*; D013315:Stress, Psychological / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology
chemical_list: D000929:Antidepressive Agents, Tricyclic; D012333:RNA, Messenger; D044282:Receptor, Serotonin, 5-HT1A; D007099:Imipramine
keywords: 5-HT1A receptor; Antidepressant; DNA methylation; Epigenetics; Gene expression; Plasticity; Raphe; Serotonin; Sp4; UCMS