Loss of MeCP2 in adult 5-HT neurons induces 5-HT1A autoreceptors, with opposite sex-dependent anxiety and depression phenotypes

Sci Rep. 2018 Apr 10;8(1):5788. doi: 10.1038/s41598-018-24167-8.


The 5-HT1A autoreceptor mediates feedback inhibition of serotonin (5-HT) neurons, and is implicated in major depression. The human 5-HT1A gene (HTR1A) rs6295 risk allele prevents Deaf1 binding to HTR1A, resulting in increased 5-HT1A autoreceptor transcription. Since chronic stress alters HTR1A methylation and expression, we addressed whether recruitment of methyl-binding protein MeCP2 may alter Deaf1 regulation at the HTR1A locus. We show that MeCP2 enhances Deaf1 binding to its HTR1A site and co-immunoprecipitates with Deaf1 in cells and brain tissue. Chromatin immunoprecipitation assays showed Deaf1-dependent recruitment of MeCP2 to the mouse HTR1A promoter, and MeCP2 modulated human and mouse HTR1A gene transcription in a Deaf1-dependent fashion, enhancing Deaf1-induced repression at the Deaf1 site. To address the role of MeCP2 in HTR1A regulation in vivo, mice with conditional knockout of MeCP2 in adult 5-HT neurons (MeCP2 cKO) were generated. These mice exhibited increased 5-HT1A autoreceptor levels and function, consistent with MeCP2 enhancement of Deaf1 repression in 5-HT neurons. Interestingly, female MeCP2-cKO mice displayed reduced anxiety, while males showed increased anxiety and reduced depression-like behaviors. These data uncover a novel role for MeCP2 in 5-HT neurons to repress HTR1A expression and drive adult anxiety- and depression-like behaviors in a sex-specific manner.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anxiety / genetics
  • Anxiety / metabolism*
  • Brain / metabolism
  • Cell Line
  • DNA-Binding Proteins
  • Depression / genetics
  • Depression / metabolism*
  • Female
  • Gene Expression Regulation
  • HEK293 Cells
  • Humans
  • Male
  • Methyl-CpG-Binding Protein 2 / metabolism*
  • Mice
  • Mice, Knockout
  • Nuclear Proteins / metabolism
  • Promoter Regions, Genetic
  • Receptor, Serotonin, 5-HT1A / genetics*
  • Serotonergic Neurons / metabolism*
  • Sex Factors
  • Transcription Factors / metabolism


  • DEAF1 protein, human
  • DNA-Binding Proteins
  • Deaf1 protein, mouse
  • Methyl-CpG-Binding Protein 2
  • Nuclear Proteins
  • Transcription Factors
  • Receptor, Serotonin, 5-HT1A