Chronic mild stress and antidepressant treatment alter 5-HT1A receptor expression by modifying DNA methylation of a conserved Sp4 site

Neurobiol Dis. 2015 Oct;82:332-341. doi: 10.1016/j.nbd.2015.07.002. Epub 2015 Jul 15.


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.

Keywords: 5-HT1A receptor; Antidepressant; DNA methylation; Epigenetics; Gene expression; Plasticity; Raphe; Serotonin; Sp4; UCMS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidepressive Agents, Tricyclic / pharmacology*
  • Chronic Disease
  • Conserved Sequence
  • CpG Islands
  • DNA Methylation / drug effects*
  • DNA Methylation / physiology
  • Depressive Disorder / drug therapy*
  • Depressive Disorder / genetics
  • Depressive Disorder / metabolism*
  • Disease Models, Animal
  • Dorsal Raphe Nucleus / drug effects
  • Dorsal Raphe Nucleus / metabolism
  • Imipramine / pharmacology
  • Male
  • Mice, Inbred BALB C
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / metabolism
  • Promoter Regions, Genetic
  • RNA, Messenger / metabolism
  • Receptor, Serotonin, 5-HT1A / genetics*
  • Receptor, Serotonin, 5-HT1A / metabolism*
  • Stress, Psychological / drug therapy
  • Stress, Psychological / genetics
  • Stress, Psychological / metabolism
  • Transcription, Genetic / drug effects
  • Transcription, Genetic / physiology


  • Antidepressive Agents, Tricyclic
  • RNA, Messenger
  • Receptor, Serotonin, 5-HT1A
  • Imipramine