Major depressive disorder (MDD), is a prevalent mood disorder that associates with differential prefrontal brain expression patterns1. Treatment of MDD includes a variety of biopsychosocial approaches, but in medical practice, antidepressant drugs are the most common treatment for depressive episodes, and not surprisingly, they are among the most prescribed medications in North America2,3. While they are clearly effective, particularly for moderate to severe depressive episodes, there is important variability in how individuals respond to antidepressant treatment. Failure to respond has important individual, economic and social consequences for patients and their families4. Several lines of evidence demonstrate that genes are regulated through the activity of microRNAs (miRNAs), which act as fine–tuners and on–off switches in gene expression patterns5–7. Here we report on complementary studies using postmortem human brain samples, cellular assays and samples from clinical trials of depressed patients, and show that miR-1202, a miRNA specific to primates and enriched in the human brain, is differentially expressed in depressed individuals. Additionally, miR-1202 regulates the expression of the Metabotropic Glutamate Receptor 4 (GRM4) gene and predicts antidepressant response at baseline. These results suggest that miR-1202 is associated with the pathophysiology of depression and is a potential target for novel antidepressant treatments.

Adolescence is a period of heightened susceptibility to psychiatric disorders of medial prefrontal cortex (mPFC) dysfunction and cognitive impairment. mPFC dopamine (DA) projections reach maturity only in early adulthood, when their control over cognition becomes fully functional. The mechanisms governing this protracted and unique development are unknown. Here we identify dcc as the first DA neuron gene to regulate mPFC connectivity during adolescence and dissect the mechanisms involved. Reduction or loss of dcc from DA neurons by Cre-lox recombination increased mPFC DA innervation. Underlying this was the presence of ectopic DA fibers that normally innervate non-cortical targets. Altered DA input changed the anatomy and electrophysiology of mPFC circuits, leading to enhanced cognitive flexibility. All phenotypes only emerged in adulthood. Using viral Cre, we demonstrated that dcc organizes mPFC wiring specifically during adolescence. Variations in DCC may determine differential predisposition to mPFC disorders in humans. Indeed, DCC expression is elevated in brains of antidepressant-free subjects who committed suicide.

BACKGROUD Variations in the expression of the Netrin-1 guidance cue receptor DCC (Deleted in colorectal cancer) appear to confer resilience or susceptibility to psychopathologies involving prefrontal cortex (PFC) dysfunction. METHODS Using postmortem brain tissue, mouse models of defeat stress, and in vitro analysis, we assessed microRNA (miRNA) regulation of DCC and whether changes in DCC levels in the PFC lead to vulnerability to depression-like behaviors. RESULTS We identify miR-218 as a posttranscriptional repressor of DCC, and detect co-expression of DCC and miR-218 in pyramidal neurons of human and mouse PFC. We find that exaggerated expression of DCC and reduced levels of miR-218 in the PFC are consistent traits of mice susceptible to chronic stress and of major depressive disorder in humans. Remarkably, upregulation of Dcc in mouse PFC pyramidal neurons causes vulnerability to stress-induced social avoidance and anhedonia. CONCLUSION These data are the first demonstration of miRNA regulation of DCC and suggest that, by regulating DCC, miR-218 may be a switch of susceptibility versus resilience to stress-related disorders.