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

Angélica Torres-Berrío, Juan Pablo Lopez, Rosemary C. Bagot, Dominique Nouel, Gregory Dal Bo, Santiago Cuesta, Lei Zhu, Colleen Manitt, Conrad Eng, Helen M. Cooper, Kai Florian Storch, Gustavo Turecki, Eric J. Nestler, Cecilia Flores

Research output: Contribution to journalArticlepeer-review

102 Scopus citations

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.

Original languageEnglish
Pages (from-to)306-315
Number of pages10
JournalBiological Psychiatry
Volume81
Issue number4
DOIs
StatePublished - 15 Feb 2017

Keywords

  • Chronic social defeat stress
  • Guidance cue
  • Major depressive disorder
  • Neurodevelopment
  • Resilience
  • microRNA

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