DCC Confers Susceptibility to Depression-like Behaviors in Humans and Mice and Is Regulated by miR-218.

TitleDCC Confers Susceptibility to Depression-like Behaviors in Humans and Mice and Is Regulated by miR-218.
Publication TypeJournal Article
Year of Publication2017
AuthorsTorres-Berrío A, Lopez JPablo, Bagot RC, Nouel D, Dal Bo G, Cuesta S, Zhu L, Manitt C, Eng C, Cooper HM, Storch K-F, Turecki G, Nestler EJ, Flores C
JournalBiol Psychiatry
Volume81
Issue4
Pagination306-315
Date Published2017 Feb 15
ISSN1873-2402
Abstract

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: With the use of 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 identified miR-218 as a posttranscriptional repressor of DCC and detected coexpression of DCC and miR-218 in pyramidal neurons of human and mouse PFC. We found 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.CONCLUSIONS: These data are the first demonstration of microRNA regulation of DCC and suggest that, by regulating DCC, miR-218 may be a switch of susceptibility versus resilience to stress-related disorders.

DOI10.1016/j.biopsych.2016.08.017
Alternate JournalBiol. Psychiatry
PubMed ID27773352
PubMed Central IDPMC5239724
Grant ListP50 MH096890 / MH / NIMH NIH HHS / United States
R01 DA037911 / DA / NIDA NIH HHS / United States

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