Abstract
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.
Highlights
Depression is a complex mental health disorder that affects 16–20% of the population[8,9]
Because methylation of the Deaf[1] site of the 5-HT1A gene is associated with negative symptoms of schizophrenia, we addressed whether its methylation affects Deaf[1] and/or MeCP2 recruitment, since MeCP2 binds to methylated DNA
Since yeast lack endogenous DNA methylase, the DNA methylase transferase MSssI was transduced for comparison of methylated and non-methylated states
Summary
Depression is a complex mental health disorder that affects 16–20% of the population[8,9]. The loss of Deaf[1] led to a decrease in cortical 5-HT1A receptors, by preventing Deaf[1] enhancer function that is seen in non-serotonergic neuronal cells[36]. These data suggest that Deaf[1] bidirectionally regulates the HTR1A gene in different brain regions but is unable to do so at the G(-1019) variant. We studied the potential role of MeCP2 in regulating HTR1A gene expression, its interaction with Deaf[1], and the functional effects of conditionally knocking out MeCP2 in 5-HT-producing neurons on 5-HT1A autoreceptor expression. Our findings indicate that while Deaf[1] and MeCP2 interact to regulate 5-HT1A receptor gene expression in 5-HT neurons, MeCP2 has sex-dependent actions that impact behavior
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