Epigenetic intersection of BDNF Val66Met genotype with premenstrual dysphoric disorder transcriptome in a cross-species model of estradiol add-back

Abstract

Premenstrual dysphoric disorder (PMDD) affects over 5% of women, with symptoms similar to anxiety and major depression, and is associated with differential sensitivity to circulating ovarian hormones. Little is known about the genetic and epigenetic factors that increase the risk to develop PMDD. We report that 17β-estradiol (E2) affects the behavior and the epigenome in a mouse model carrying a single-nucleotide polymorphism of the brain-derived neurotrophic factor gene (BDNF Val66Met), in a way that recapitulates the hallmarks of PMDD. Ovariectomized mice heterozygous for the BDNF Met allele (Het-Met) and their matched wild-type (WT) mice were administered estradiol or vehicle in drinking water for 6 weeks. Using the open field and the splash test, we show that E2 add-back induces anxiety-like and depression-like behavior in Het-Met mice, but not in WT mice. RNA-seq of the ventral hippocampus (vHpc) highlights that E2-dependent gene expression is markedly different between WT mice and Het-Met mice. Through a comparative whole-genome RNAseq analysis between mouse vHpc and lymphoblastoid cell line cultures from control women and women with PMDD, we discovered common epigenetic biomarkers that transcend species and cell types. Those genes include epigenetic modifiers of the ESC/E(Z) complex, an effector of response to ovarian steroids. Although the BDNF Met genotype intersects the behavioral and transcriptional traits of women with PMDD, we suggest that these similarities speak to the epigenetic factors by which ovarian steroids produce negative behavioral effects.

Pharmacological sex hormone manipulation as a risk model for depression

“…Recent studies have pointed to molecular mechanisms, in terms of gene expression and epigenetic modifications, of such sensitivity to ovarian hormone changes, in particular estrogen sensitivity (Guintivano, Arad, Gould, Payne, & Kaminsky, 2014; Mehta et al., 2014). Finally, the ovarian hormone sensitivity hypothesis is indirectly strengthened by observations in women with premenstrual dysphoric disorder (PMDD) who indeed develop depressive symptoms when exposed to ovarian steroid hormone replacement after a period of hormonal suppression (Schmidt et al., 2017), which again seem to involve epigenetic mechanisms related to estradiol (Marrocco et al., 2018).…”

Klerman's “credo” reconsidered:neo‐Kraepelinianism, Spitzer's views, and what we can learn from the past

“…Researchers then established that the greater reactivity was due to specific genetic variations that led to overexpression of some cellular responses and underexpression of others 129 . These findings were replicated in animal models of PMDD 130 . This research revealed an underlying dysfunction of genetic response to hormone fluctuation that supports the idea that PMDD is a categorical disorder.…”

Recent advances in understanding/management of premenstrual dysphoric disorder/premenstrual syndrome

“…In a mouse model, a single-nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene induces anxiety-like and depression-like behavior in response to estradiol administration, similarly to what occurs in women with PMDD 83 .…”

“…Finally, recent findings focused on genetic variations involving the GABAergic system, establishing for the first time an association between PMDD and copy number variations in the GABRB2 gene encoding for a GABA-A receptor subunit 84 . Thus, genetic and epigenetic studies may shed light on a possible behavioral sensitivity to ovarian sex steroids and may pave the way to novel targets for therapy 83 .…”