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Free keywords:
Early life adversity, Early life stress, Major depression, Epigenetic programming, HPA axis, Mecp2
Abstract:
Early life adversity (ELA) is an important risk factor for the
manifestation of various psychiatric disorders later in life. Prenatal
and postnatal brain development comprises a time of heightened neuronal
plasticity, and ELA during these periods can lead to long-lasting
changes in the formation of neuronal activity-dependent circuitries and
structures in conjunction with epigenetic marking of genes important to
cognition, mood, and behavior. Among various epigenetic marks, DNA
methylation is the best characterized besides histone modifications and
chromatin remodeling factors. ELA during critical windows of development
can cause sustained deregulation of the hypothalamic-pituitary-adrenal
(HPA) axis, a major mediator of the stress response, whose deregulation
during the course of major depression is thought to recall ELA exposure.
ELA in mice evokes epigenetic programming of the hypothalamic
neuropeptide arginine vasopressin (Avp), a critical driver of the HPA
axis, with the epigenetic reader methyl-CpG-binding protein 2 (Mecp2)
playing an important role in the establishment and maintenance of
ELA-dependent epigenetic marks. Similarly, Mecp2 mediates epigenetic
programming of pituitary pro-opiomelanocortin (Pomc), a downstream
effector of the neuronal stress response. Overall, these studies suggest
that Mecp2 integrates ELA at different levels of the HPA axis and point
to the need for timely therapeutic interventions to prevent the
progression of potentially harmful epigenetic marks.
