The microRNA network is altered in anterior cingulate cortex of patients with unipolar and bipolar depression

Abstract

MicroRNAs (miRNAs) are small, non-coding RNAs acting as post-transcriptional regulators of gene expression. Though implicated in multiple CNS disorders, miRNAs have not been examined in any psychiatric disease state in anterior cingulate cortex (AnCg), a brain region centrally involved in regulating mood. We performed qPCR analyses of 29 miRNAs previously implicated in psychiatric illness (major depressive disorder (MDD), bipolar disorder (BP) and/or schizophrenia (SZ)) in AnCg of patients with MDD and BP versus controls. miR-132, miR-133a and miR-212 were initially identified as differentially expressed in BP, miR-184 in MDD and miR-34a in both MDD and BP (although none survived multiple correction testing and must be considered preliminary). In silico target prediction algorithms identified putative targets of differentially expressed miRNAs. Nuclear Co-Activator 1 (NCOA1), Nuclear Co-Repressor 2 (NCOR2) and Phosphodiesterase 4B (PDE4B) were selected based upon predicted targeting by miR-34a (with NCOR2 and PDE4B both targeted by miR-184) and published relevance to psychiatric illness. Luciferase assays identified PDE4B as a target of miR-34a and miR-184, while NCOA1 and NCOR2 were targeted by miR-34a and 184, respectively. qPCR analyses were performed to determine whether changes in miRNA levels correlated with mRNA levels of validated targets. NCOA1 showed an inverse correlation with miR-34a in BP, while NCOR2 demonstrated a positive correlation. In sum, this is the first study to demonstrate miRNA changes in AnCg in psychiatric illness and validate miR-34a as differentially expressed in CNS in MDD. These findings support a mechanistic role for miRNAs in the regulation of stress-responsive genes disrupted in psychiatric illness.

Increased Levels of miR-30e, miR-132, miR-185, and miR- 212 at Baseline and Increased Brain-derived Neurotrophic Factor Protein and mRNA Levels after Treatment in Patients with Major Depressive Disorder

“…In a postmortem study, miR-132 and miR-212 were initially identified as differentially expressed in bipolar disorder [22]. In patients with postpartum psychosis, miR-212 was found to be decreased in monocytes [23].…”

Changes in Non-Coding RNA in Depression and Bipolar Disorder: Can They Be Used as Diagnostic or Theranostic Biomarkers?

“…However, another study failed to detect a change in miR-34a in the anterior cingulate in MDD but did report an increase in that miRNA in their cerebellum [62]. Changes in miR-34a were only found in the cerebellum from drug naive subjects and, therefore, differences in subject drug treatment status could account of the discrepancies between in the two studies [44,62].…”

“…Moreover, amongst these miRNA are a few miRNA that could be making an important contribution to disrupting major signalling pathways in in MDD and BD. As such, several studies have reported altered expression of miR-124 and miR-34a miRNA in both the CNS and the periphery of subjects with MDD and BD and evidence suggests they regulate biochemical and cellular pathways thought to be relevant the neurological dysfunction in mood disorders [43][44][45]. Furthermore, given the difficulties in modelling the clinical profile of mood disorders in animals, altered levels of the primate specific miRNA, miR-1202, in MDD suggest this miRNA may be important in understanding MDD as a clinical disorder of humans [46].…”

“…miR-34b and miR-34c are reported to be increased in blood from first episode MDD [72] with miR-34c shown to be reduced by escitalopram treatment [73]. Contrasting the changes in miR-34b and miR-34c levels in the blood, it is the level of miR-34a that is reported to be lower in cerebrospinal fluid (CSF) [59] and the anterior cingulate [44] from subjects with MDD and BD; a CNS region thought to be functionally important in mood and emotional response [74]. Notably, the common decrease in miR-34a in MDD and BD in the anterior cingulate contrasted diagnosis specific decreases in miR-184 in MDD and miR-122, miR-132 and miR-133a in BD suggesting that while miR-34a may regulating abnormal pathways affected in mood disorders, these latter miRNA may be important in distinguishing the biochemical dysfunction in MDD from that in BD [44].…”

“…Functional assays of predicted miR-34a targets show that miR-34a can decrease the activity of the Nuclear Receptor Coactivator 1 (NCOA1) and the Nuclear Receptor Co-repressor 2 (NCOR2), in vitro [44]. These genes act to regulate the transcriptional machinery of the cell.…”