Long-term lithium and valproate treatment have also been shown to alter a number of miRNAs; however, 9 miRNAs (let-7b, NLG-8189 let-7c,

miR-105, miR-128a, miR-24a, miR-30c, miR-34a, miR221, and miR-144) were regulated by both lithium and valproate. The most significant signaling pathways that are targeted by these miRNAs are the PKC, PTEN, ERK-MAP kinase, Wnt/β-catenin, and β-adrenergic pathways. Some of these have been shown Inhibitors,research,lifescience,medical to be altered in MDD and bipolar disorder.154 Lithium- and valproate induced downregulated miR-128a, miR-24, and miR-34a significantly upregulated hippocampal protein levels of DPP10, GRM7, and THRB. Among these proteins, GRM7 has emerged as a novel candidate gene for bipolar disorder.155 miRNAs in MDD subjects

One of the approaches that have been taken Inhibitors,research,lifescience,medical to directly assess the status of miRNAs in psychiatric illnesses is to examine the postmortem brain. Using this approach, we recently profiled miRNA expression in the prefrontal cortex of depressed subjects who had died by suicide (Table I).156 We took several different approaches to analyzing the data. When we analyzed miRNA expression globally, we found that 21 miRNAs were significantly downregulated in the MDD group. We also found that 24 miRNAs were downregulated Inhibitors,research,lifescience,medical by 30% (although not statistically significant), suggesting a global Inhibitors,research,lifescience,medical downregulation of miRNA

levels in the MDD group. When analyzed individually, we found that almost half of the downregulated miRNAs were encoded at chromosomal loci near other miRNAs and are possibly transcribed by the same pri-miRNA gene transcripts (mir-1 42 -5p and 142-3p; mir-494, 376a*, 496, and 369-3p; mir-23b, 27b and 24-1*; mir-34b* and 34c; mir-17* and 20a). In addition, Inhibitors,research,lifescience,medical three pairs of miRNAs were encoded at distances greater than 100 kb, but still lie within the same chromosomal region (mir-424 and 20b at Xq26.2-3, 377 kb apart; mir-142 and 301a at 17q22, 820 kb apart; mir-3245p and 497 at 17pl3.1, 205 kb apart). This suggests that at least some of the downregulated miRNA expression is due to decreased transcription. Many of the downregulated miRNAs also all shared 5′ seed sequences that are involved in target recognition. For example, identical seed sequences are shared by: (i) mir-20a and 20b; (ii) mir-301 a and 130a; and (iii) mir-424 and 497. In addition, a 6-mer nucleotide motif is shared by mir-34a, 34b*, and 34c, and strikingly, a 5-mer motif (AGUGC) within the 5′ seed is shared by 5 of the affected miRNAs (mir-148b, 301a, 130a, 20a, and 20b) that is predicted to bind Alu sequences within the 3* UTR region of target mRNAs. This suggests that the downregulated miRNAs should exhibit extensive overlap among their mRNA targets.