132 Turner et al133 recently predicted several possible miRNA binding sites within the GR first exon, suggesting further regulation of GR genes by miRNAs. TABLE I. miRNAs implicated in stress and depression. miRNAs in response to stress Several types of stressors have been utilized to examine how miRNAs respond to stressors. Interestingly, acute and chronic restrained stress cause differential changes in miRNA expression in a brain region-specific manner (Table I). 134 For example, acute stress Inhibitors,research,lifescience,medical induces a transient increase in the expression of

selected miRNAs (miR-9, miR-9*, miR-26b, miR-29b, miR-30b, miR-30c, miR-30e, miR-125a, miR-126-3p, miR-129-3p, miR-207, miR-212, miR-351, miR-423, miR-487b, miR-494, miR-690, miR691, miR-709, miR-711, and Let-7 a-e) in the frontal cortex, but not the hippocampus. Some of them (let-7a, miR-9, miR-26a/b, miR-30b/c, and miR-125a) show an increase in their expression Inhibitors,research,lifescience,medical 5 days after acute stress; however, their expression levels are not altered after repeated restraint. These results suggest that acute stress modulates miRNA expression quickly to external stimuli by changing their synaptic efficacy through regulation

of localized mRNA translation. Using psychological stress (acute or chronic immobilization), Meerson et al135 examined miRNA expression in the central amygdala and the Cornu Ammonis area 1 (CA1) region of the hippocampus of Inhibitors,research,lifescience,medical rats subjected to acute or chronic immobilization stress Inhibitors,research,lifescience,medical (Table I). They found that the expression of several miRNAs was differentially altered during acute and chronic stress, with chronic stress causing much larger changes than acute stress. Some of the miRNAs that were altered during acute and chronic stress include: miR-134, miR-183, miR-132, Let-7a-l, miR-9-1, and miR-124a-l. Interestingly, except for miR-Let-7a-l, the expression of stress-responsive miRNAs were different in the two analyzed brain regions. In the CA1 region, miR-376b

and miR-208 increased whereas miR-9-1 decreased Inhibitors,research,lifescience,medical under both acute and chronic stress conditions. Stressresponsive miR-134 and miR-183 target many splicing factors, such as SC35, SRP46, and SFRSll. SC35 promotes the Akt inhibitor alternative splicing of acetylcholinesterase (AChE) from the synapse-associated isoform AChE-S to soluble AChE-R protein and the expression of SC35 is increased during stress. Thus, by regulating splicing factors and their almost targets, miR-183 and miR-134 may modify both alternative splicing and cholinergic neurotransmission in the stressed brain. In addition, one of the targets of miR-183 is profilin 2 mRNA, which regulates dendritic spine morphology in neurons. Interestingly, neurotransmitter homeostasis and behavior are severely affected in profilin 2 knockdown mice136 and prolifin 2 (PFN2) expression is increased in lymphoblastoid cell lines of monozygotic twin pairs discordant for bipolar disorder.