Dataset Information

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

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.

SUBMITTER: Torres-Berrio A

PROVIDER: S-EPMC5239724 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Torres-Berrío Angélica A Lopez Juan Pablo JP Bagot Rosemary C RC Nouel Dominique D Dal Bo Gregory G Cuesta Santiago S Zhu Lei L Manitt Colleen C Eng Conrad C Cooper Helen M HM Storch Kai-Florian KF Turecki Gustavo G Nestler Eric J EJ Flores Cecilia C

Biological psychiatry 20160818 4

<h4>Backgroud</h4>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.<h4>Methods</h4>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.<h4>Results</ ...[more]

PMID: 27773352

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Project description:Understanding the epigenetic role of microRNAs (miRNAs) has been a critical development in the field of neuropsychiatry and in understanding their underlying pathophysiology. Abnormalities in miRNA expression are often seen as key to the pathogenesis of many stress-associated mental disorders, including major depressive disorder (MDD). Recent advances in omics biology have further contributed to this understanding and expanded the role of miRNAs in networking a diverse array of molecular pathways, which are essentially related to the stress adaptivity of a healthy brain. Studies have highlighted the role of many such miRNAs in causing maladaptive changes in the brain's stress axis. One such miRNA is miR-218, which is debated as a critical candidate for increased stress susceptibility. miR-218 is expressed throughout the brain, notably in the hippocampus and prefrontal cortex (PFC). It is expressed at various levels through life stages, as seen by adolescent and adult animal models. Until now, a minimal number of studies have been conducted on human subjects to understand its role in stress-related abnormalities in brain circuits. However, several studies, including animal and cell-culture models, have been used to understand the impact of miR-218 on stress response and hypothalamic-pituitary-adrenal (HPA) axis function. So far, expression changes in this miRNA have been found to regulate signaling pathways such as glucocorticoid signaling, serotonergic signaling, and glutamatergic signaling. Recently, the developmental role of miR-218 has generated interest, given its increasing expression from adolescence to adulthood and targeting the Netrin-1/DCC signaling pathway. Since miR-218 expression affects neuronal development and plasticity, it is expected that a change in miR-218 expression levels over the course of development may negatively impact the process and make individuals stress-susceptible in adulthood. In this review, we describe the role of miR-218 in stress-induced neuropsychiatric conditions with an emphasis on stress-related disorders.

Dataset Information

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

Backgroud

Methods

Results

Conclusions

Publications

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

Similar Datasets

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