The microRNA regulatory network is altered in anterior cingulate cortex of patients with unipolar and bipolar depression
Azevedo JA, Carter BS, Meng F, Turner DL, Dai M, Schatzberg AF, Barchas JD, Jones EG, Bunney WE, Myers RM, Akil H, Watson SJ, Thompson RC
Society for Neuroscience. 2015.
MicroRNAs are a class of small, non-coding RNAs that canonically act as post-transcriptional regulators of gene expression. Given that microRNAs (miRNA) are heavily enriched in the CNS and regulate many CNS processes, they have garnered intense interest, particularly in their relevance to CNS disorders. Multiple miRNAs have been shown to vary as a function of psychiatric disease state in several psychiatrically-relevant brain regions. However, these microRNAs have not been examined in any psychiatric disease state in the anterior cingulate cortex (AnCg), a brain region centrally involved in the regulation of mood and affect. Here we performed qPCR expression analyses of 29 miRNAs previously implicated in psychiatric illness (e.g. MDD, BP and/or schizophrenia) in AnCg of patients with MDD and BP versus control patients. Five microRNAs were differentially expressed in disease states: three in the BP cohort, one in the MDD cohort, and one across both states. In silico target prediction algorithms were used to identify putative targets of differentially expressed miRNAs and three mRNA candidates were selected based upon their previously published relevance to psychiatric illness. Luciferase reporter assays employing 3’ UTRs of these candidate mRNAs were used to query miRNA/mRNA interactions. Site-directed mutagenesis of the putative seed domains alleviated each miRNA repression, validating these direct miRNA/mRNA interactions. Following target validations qPCR analyses were performed to determine whether changes in miRNA levels were correlated with changes in steady-state mRNA levels of these validated targets. Of the three mRNAs examined, one mRNA was overexpressed in our BP cohort, one was repressed in our MDD cohort, and one was unchanged in either disease state. In sum, this is the first study to demonstrate miRNA changes in AnCg as a function of psychiatric disease and 2) validate a miRNA as differentially expressed in both MDD and BP cohorts. Taken together, these findings support a mechanistic role for miRNAs in gene expression changes previously observed in psychiatric illness.