Epigenetics of depression
[1] Early life stresses that could lead to major depressive disorder include periodic maternal separation, child abuse, divorce, and loss.
[2][3] These factors can result in epigenetic marks that can alter gene expression and impact the development of key brain regions such as the hippocampus.
[4][2] Epigenetic factors, such as DNA methylation, could serve as potential predictors for the effectiveness of certain antidepressant treatments, as well as show associations with depression symptoms.
In the nucleus accumbens (NaC), it is generally found that H3K14 acetylation decreases after chronic stress (used to produce a depression-like state in rodent model systems).
Depolarization of neurons causing an increase in calcium leads to the phosphorylation of MeCP2, which results in a decrease in the binding of MeCP2 to BDNF promoter IV.
Also, there was found to be increased methylation of BDNF region IV CpGs in the Wernicke area of the brain in suicidal individuals.
Previous studies have found that in MeCP2 knockout mice, the release and trafficking of BDNF within the neurons are significantly decreased in the hippocampus.
[16] It was found that pregnant mice in early gestation stage who were exposed to chronic stress produced offspring with a decreased methylation of the CRF promoter in the hypothalamus area.
The higher levels of the HPA axis in response to chronic stress can also cause damage to the hippocampus region of the brain.
Glial cell-derived neurotrophic factor (GDNF) is a protein that aids in the survival and differentiation of dopaminergic neurons.
[4] It has also been shown that increased GDNF expression in the ventral tegmental area is present in mice that are not susceptible to social defeat stress by promoting the survival of neurons.
[18][19] The ventral tegmental area and nucleus accumbens network of the mesolimbic dopamine system is thought to be involved in the resistance and susceptibility to chronic stress (which leads to depressed behavior).
In rats, it has been shown that individuals less susceptible to depressive behavior have increased binding of NGFI-A to the promoter region of the GR gene, specifically in the hippocampus.
[25] Furthermore, the methylation of the promoter region results in a decrease in recruitment of the CREB-binding protein, which has histone acetyltransferase ability.
This results in less acetylation of the histones, which has been shown to be a modification that takes place within individuals less susceptible to depression.
Through computational methodology, epigenetics has been found to play a critical role in mood disorder susceptibility and development, and has also been shown to mediate treatment response to SSRI medications.
SSRI medications including fluoxetine, paroxetine, and escitalopram reduce gene expression and enzymatic activity related to methylation and acetylation pathways in numerous brain regions implicated in patients with major depression.
[26] Pharmacogenetic research has focused on epigenetic factors related to BDNF, which has been a biomarker for neuropsychiatric diseases.
[26] In addition to the BDNF gene, micro RNAs (miRNAs) play a role in mood disorders, and transcript levels are suggested in SSRI treatment efficacy.
Post-mortem work in patients with major depressive disorder, as well as other psychiatric diseases, show that miRNAs play a critical role in regulating brain structure via synaptic plasticity and neurogenesis.
Increased hippocampal MIR-16 inhibits proteins which promote neurogenesis including the serotonin transporter (SERT), which is the target of SSRI therapeutics.
[26] SSRI medications increase neurogenesis in the hippocampus by reductions in MIR-16, thereby restoring hippocampal neuronal activity following treatment in patients with neuropsychiatric disorders.
[34] It is thought that this is happening due to an interaction between the response element of GR and the acetyltransferase, CREB Binding Protein.
Therefore, this antidepressant, by increasing acetylation, works to lessen the HPA response, and as a result, decrease depressive symptoms.
Research shows that antidepressants make epigenetic changes to gene transcription thus altering signaling.
HDAC inhibitors can decrease gene transcription in the hippocampus and prefrontal cortex that is increased as a characteristic of depression.
Some studies show that administration of HDAC inhibitors like vorinostat and romidepsin, hematologic cancer drugs, can augment the effect of other antidepressants.
