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Biol Psychiatry. 2017 Feb 15;81(4):306-315. doi: 10.1016/j.biopsych.2016.08.017. Epub 2016 Aug 18.

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

Author information

1
Integrated Program in Neuroscience, Montréal, Québec, Canada; Douglas Mental Health University Institute; Montréal, Québec, Canada.
2
Department of Human Genetics; Montréal, Québec, Canada; McGill Group for Suicide Studies, Montréal, Québec, Canada.
3
Departments of Psychology ; Montréal, Québec, Canada.
4
Douglas Mental Health University Institute; Montréal, Québec, Canada.
5
Douglas Mental Health University Institute; Montréal, Québec, Canada; Département de Toxicologie et risques chimiques, IRBA, Brétigny sur Orge, France.
6
Psychiatry, McGill University; Montréal, Québec, Canada; Douglas Mental Health University Institute; Montréal, Québec, Canada.
7
Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia.
8
Psychiatry, McGill University; Montréal, Québec, Canada; Douglas Mental Health University Institute; Montréal, Québec, Canada; McGill Group for Suicide Studies, Montréal, Québec, Canada.
9
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
10
Psychiatry, McGill University; Montréal, Québec, Canada; Douglas Mental Health University Institute; Montréal, Québec, Canada. Electronic address: cecilia.flores@mcgill.ca.

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.

KEYWORDS:

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

PMID:
27773352
PMCID:
PMC5239724
DOI:
10.1016/j.biopsych.2016.08.017
[Indexed for MEDLINE]
Free PMC Article

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