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

doi:10.1016/j.biopsych.2016.08.017

Biological Psychiatry

Volume 81, Issue 4, 15 February 2017, Pages 306-315

https://doi.org/10.1016/j.biopsych.2016.08.017 Get rights and content

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.

Section snippets

Methods and Materials

Detailed description of procedures is provided in Supplemental Methods and Materials.

Results

First, we tested the validity of our previous finding (4) by measuring DCC mRNA expression in an independent PFC sample derived from postmortem brains of 11 antidepressant-free subjects with MDD who committed suicide and of 12 psychiatrically healthy sudden death control subjects (Figure 1A). Indeed, we confirmed increased DCC mRNA expression (~40%) in the MDD group compared with control subjects (Figure 1B). Despite differences in sample size, the magnitude of DCC overexpression is similar

Discussion

An understanding of the pathophysiology of stress-related disorders, including MDD, is necessary for developing novel preventive strategies and overcoming the lack of effectiveness of current treatments. One way to advance this knowledge is to identify candidate molecular determinants of vulnerability and of resiliency using postmortem human brain tissue of subjects who manifest such conditions. Another strategy is to take advantage of preclinical models to characterize the enduring plastic

Acknowledgments and Disclosures

This work was funded by Canadian Institute for Health Research Grant No. MOP-74709 (to CF), the National Institute on Drug Abuse Grant No. R01DA037911 (to CF), the Natural Science and Engineering Research Council of Canada Grant No. 2982226 (to CF), and National Institute of Mental Health Grant No. P50MH096890 (to EJN).

AT-B, JPL, and CF designed the project. AT-B and JPL performed expression experiments with postmortem human brain samples and mouse brain tissue. AT-B performed stereotaxic

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People with severe mental illness have a higher risk of cardiometabolic disease than the general population. Traditionally attributed to sociodemographic, behavioural factors and medication effects, recent genetic studies have provided evidence of shared biological mechanisms underlying mental illness and cardiometabolic disease. We aimed to determine whether signals in the DCC locus, implicated in psychiatric and cardiometabolic traits, were shared or distinct.
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Multiple genome studies have discovered that variation in deleted in colorectal carcinoma (Dcc) at transcription and translation level were associated with the occurrences of psychiatric disorders. Yet, little is known about the function of Dcc in schizophrenia (SCZ)-related behavioral abnormalities and the efficacy of antipsychotic drugs in vivo. Here, we used an animal model of prefrontal cortex-specific knockdown (KD) of Dcc in adult C57BL/6 mice to study the attention deficits and impaired locomotor activity. Our results supported a critical role of Dcc deletion in SCZ-related behaviors. Notably, olanzapine rescued the SCZ-related behaviors in the MK801-treated mice but not in the cortex-specific Dcc KD mice, indicating that Dcc play a critical in the mechanism of antipsychotic effects of olanzapine. Knockdown of Dcc in prefrontal cortex results in glutamatergic dysfunction, including defects in glutamine synthetase and postsynaptic maturation. As one of the major risk factors of the degree of antipsychotic response, Dcc deletion-induced glutamatergic dysfunction may be involved in the underlying mechanism of treatment resistance of olanzapine. Our findings identified Dcc deletion-mediated SCZ-related behavioral defects, which serve as a valuable animal model for study of SCZ and amenable to targeted investigations in mechanistic hypotheses of the mechanism underlying glutamatergic dysfunction-induced antipsychotic treatment resistance.
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¹: AT-B and JPL contributed equally to this work

View full text

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

Abstract

Backgroud

Methods

Results

Conclusions

Section snippets

Methods and Materials

Results

Discussion

Acknowledgments and Disclosures

Prog Biophys Mol Biol

Cell

Neuron

Cell

Mech Dev

J Biomed Inform

Cell

Prog Brain Res

Netrins and their receptors

Adv Exp Med Biol

Guidance molecules in synapse formation and plasticity

Cold Spring Harb Perspect Biol

dcc orchestrates the development of the prefrontal cortex during adolescence and is altered in psychiatric patients

Transl Psychiatry

Role of netrin-1 in the organization and function of the mesocorticolimbic dopamine system

J Psychiatry Neurosci

Netrin-1 receptor-deficient mice show enhanced mesocortical dopamine transmission and blunted behavioural responses to amphetamine

Eur J Neurosci

Altered netrin-1 receptor expression in dopamine terminal regions following neonatal ventral hippocampal lesions in the rat

Synapse

miR-1202 is a primate-specific and brain-enriched microRNA involved in major depression and antidepressant treatment

Nat Med

Little things on which happiness depends: MicroRNAs as novel therapeutic targets for the treatment of anxiety and depression

Mol Psychiatry

When less is more–MicroRNAs and psychiatric disorders

Acta Psychiatr Scand

The emerging role of MicroRNA in schizophrenia

CNS Neurol Disord Drug Targets

Epigenetics, microRNA, and addiction

Dialogues Clin Neurosci

Deleted in colorectal carcinoma suppresses metastasis in p53-deficient mammary tumours

Nature

A standardized protocol for repeated social defeat stress in mice

Nat Protocols

Paxinos and Franklin’s the Mouse Brain in Stereotaxic Coordinates

Peri-pubertal emergence of UNC-5 homologue expression by dopamine neurons in rodents

PLoS One

The microRNA.org resource: Targets and expression

Nucl Acids Res

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