Abstract
Background
Adolescence is a period of increased vulnerability to psychiatric disorders, including
depression. Discovering novel biomarkers to identify individuals who are at high risk
is very much needed. Our previous work shows that the microRNA miR-218 mediates susceptibility
to stress and depression in adulthood by targeting the netrin-1 guidance cue receptor
gene Dcc in the medial prefrontal cortex (mPFC).
Methods
Here, we investigated whether miR-218 regulates Dcc expression in adolescence and could serve as an early predictor of lifetime stress
vulnerability in male mice.
Results
miR-218 expression in the mPFC increases from early adolescence to adulthood and correlates
negatively with Dcc levels. In blood, postnatal miR-218 expression parallels changes occurring in the
mPFC. Notably, circulating miR-218 levels in adolescence associate with vulnerability
to social defeat stress in adulthood, with high levels associated with social avoidance
severity. Indeed, downregulation of miR-218 in the mPFC in adolescence promotes resilience
to stress in adulthood.
Conclusions
miR-218 expression in adolescence may serve both as a marker of risk and as a target
for early interventions.
Keywords
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References
- Practice parameter for the assessment and treatment of children and adolescents with depressive disorders.J Am Acad Child Adolesc Psychiatry. 2007; 46: 1503-1526
- The emergence of depression in adolescence: Development of the prefrontal cortex and the representation of reward.Neurosci Biobehav Rev. 2008; 32: 1-19
- Adolescent depression: Stressful interpersonal contexts and risk for recurrence.Curr Dir Psychol Sci. 2009; 18: 200-204
- Developmental trajectories during adolescence in males and females: A cross-species understanding of underlying brain changes.Neurosci Biobehav Rev. 2011; 35: 1687-1703
- Adolescent depression: Stress and reward dysfunction.Harv Rev Psychiatry. 2014; 22: 139-148
- Influence of sex and stress exposure across the lifespan on endophenotypes of depression: Focus on behavior, glucocorticoids, and hippocampus.Front Neurosci. 2015; 8: 420
- Age of onset of mental disorders: A review of recent literature.Curr Opin Psychiatry. 2007; 20: 359-364
- Meta-analysis: exposure to early life stress and risk for depression in childhood and adolescence.J Am Acad Child Adolesc Psychiatry. 2020; 59: 842-855
- Diagnostic and Statistical Manual of Mental Disorders.5th ed. DC American Psychiatric Press, Washington2013
- Review: Longitudinal trajectories of child and adolescent depressive symptoms and their predictors – A systematic review and meta-analysis.Child Adolesc Ment Health. 2018; 23: 107-120
- Unraveling the epigenetic landscape of depression: focus on early life stress.Dialogues Clin Neurosci. 2019; 21: 341-357
- Treatment resistant depression: A multi-scale, systems biology approach.Neurosci Biobehav Rev. 2018; 84: 272-288
- Longitudinal stability and developmental properties of salivary cortisol levels and circadian rhythms from childhood to adolescence.Dev Psychobiol. 2012; 54: 493-502
- Elevated morning cortisol is a stratified population-level biomarker for major depression in boys only with high depressive symptoms.Proc Natl Acad Sci U S A. 2014; 111: 3638-3643
- Childhood inflammatory markers and intelligence as predictors of subsequent persistent depressive symptoms: A longitudinal cohort study.Psychol Med. 2018; 48: 1514-1522
- Longitudinal association between inflammatory markers and specific symptoms of depression in a prospective birth cohort.Brain Behav Immun. 2019; 76: 74-81
- Persistent depressive symptoms, HPA-axis hyperactivity, and inflammation: The role of cognitive-affective and somatic symptoms.Mol Psychiatry. 2020; 25: 1130-1140
- HPA-axis reactivity interacts with stage of pubertal development to predict the onset of depression.Psychoneuroendocrinology. 2015; 55: 94-101
- DNA methylation of HPA-axis genes and the onset of major depressive disorder in adolescent girls: A prospective analysis.Transl Psychiatry. 2019; 9: 245
- The impact of the severity of early life stress on diurnal cortisol: The role of puberty.Psychoneuroendocrinology. 2017; 77: 68-74
- Predicting first onset of depression in young girls: Interaction of diurnal cortisol and negative life events.J Abnorm Psychol. 2015; 124: 850-859
- Ghrelin is a persistent biomarker for chronic stress exposure in adolescent rats and humans.Transl Psychiatry. 2018; 8: 74
- Resilience priming: Translational models for understanding resiliency and adaptation to early life adversity.Dev Psychobiol. 2019; 61: 350-375
- MicroRNA 135 is essential for chronic stress resiliency, antidepressant efficacy, and intact serotonergic activity.Neuron. 2014; 83: 344-360
- Potential use of MicroRNA for monitoring therapeutic response to antidepressants.CNS Drugs. 2017; 31: 253-262
- MicroRNA mediators of early life stress vulnerability to depression and suicidal behavior.Mol Psychiatry. 2020; 25: 308-320
- Discovery of blood transcriptomic markers for depression in animal models and pilot validation in subjects with early-onset major depression.Transl Psychiatry. 2012; 2e101
- Depressive symptoms and immune transcriptional profiles in late adolescents.Brain Behav Immun. 2019; 80: 163-169
- miR-1202 is a primate-specific and brain-enriched microRNA involved in major depression and antidepressant treatment.Nat Med. 2014; 20: 764-768
- MicroRNAs 146a/b-5 and 425-3p and 24-3p are markers of antidepressant response and regulate MAPK/Wnt-system genes.Nat Commun. 2017; 8: 15497
- DCC confers susceptibility to depression-like behaviors in humans and mice and is regulated by miR-218.Biol Psychiatry. 2017; 81: 306-315
- MiR-218: A molecular switch and potential biomarker of susceptibility to stress.Mol Psychiatry. 2019; 25: 951-964
- Dcc orchestrates the development of the prefrontal cortex during adolescence and is altered in psychiatric patients.Transl Psychiatry. 2013; 3: e338
- DCC receptors drive prefrontal cortex maturation by determining dopamine axon targeting in adolescence.Biol Psychiatry. 2017; 83: 181-192
- Making dopamine connections in adolescence.Trends Neurosci. 2017; 40: 709-719
- Genome-wide association study (GWAS) and genome-wide by environment interaction study (GWEIS) of depressive symptoms in African American and Hispanic/Latina women.Depress Anxiety. 2016; 33: 265-280
- Genome-wide analysis in UK Biobank identifies four loci associated with mood instability and genetic correlation with major depressive disorder, anxiety disorder and schizophrenia.Transl Psychiatry. 2017; 7: 1264
- A combined pathway and regional heritability analysis indicates NETRIN1 pathway is associated with major depressive disorder.Biol Psychiatry. 2017; 81: 336-346
- Convergence of evidence from a methylome-wide CpG-SNP association study and GWAS of major depressive disorder.Transl Psychiatry. 2018; 8: 162
- Genome-wide association studies of brain imaging phenotypes in UK Biobank.Nature. 2018; 562: 210-216
- Genome-wide by environment interaction studies of depressive symptoms and psychosocial stress in UK Biobank and Generation Scotland.Transl Psychiatry. 2019; 9: 14
- Leveraging polygenic functional enrichment to improve GWAS power.Am J Hum Genet. 2019; 104: 65-75
- Association of whole-genome and NETRIN1 signaling pathway–derived polygenic risk scores for major depressive disorder and white matter microstructure in the UK Biobank.Biol Psychiatry Cogn Neurosci Neuroimaging. 2019; 4: 91-100
- Genomic relationships, novel loci, and pleiotropic mechanisms across eight psychiatric disorders.Cell. 2019; 179: 1469-1482.e11
- The netrin-1/DCC guidance system: Dopamine pathway maturation and psychiatric disorders emerging in adolescence.Mol Psychiatry. 2020; 25: 297-307
- The netrin-1/DCC guidance cue pathway as a molecular target in depression: Translational evidence.Biol Psychiatry. 2020; 88: 611-624
- Non-contingent exposure to amphetamine in adolescence recruits miR-218 to regulate Dcc expression in the VTA.Neuropsychopharmacology. 2017; 43: 900-911
- Netrin-1 promotes excitatory synaptogenesis between cortical neurons by initiating synapse assembly.J Neurosci. 2013; 33: 17278-17289
- Early adolescence is a critical period for the maturation of inhibitory behavior.Cereb Cortex. 2018; 29: 3676-3686
- MicroRNA-218 regulates vascular patterning by modulation of Slit-Robo Signaling.Circ Res. 2010; 107: 1336-1344
- Hierarchical organization of guidance receptors: Silencing of netrin attraction by slit through a Robo/DCC receptor complex.Science. 2001; 291: 1928-1938
- The effect of childhood trauma on blood transcriptome expression in major depressive disorder.J Psychiatr Res. 2018; 104: 50-54
- Gene expression in blood of children and adolescents: Mediation between childhood maltreatment and major depressive disorder.J Psychiatr Res. 2017; 92: 24-30
- Distinct microRNA signature in human serum and germline after childhood trauma.medRxiv. 2020; https://doi.org/10.1101/2020.8.11.20168393
- Methylation in OTX2 and related genes, maltreatment, and depression in children.Neuropsychopharmacology. 2018; 43: 2204-2211
- Tubulin polymerization promoting protein (TPPP) gene methylation and corpus callosum measures in maltreated children.Psychiatry Res Neuroimaging. 2020; 298: 111058
- MicroRNAs as biomarkers of resilience or vulnerability to stress.Neuroscience. 2015; 305: 36-48
- MicroRNAs in major depressive disorder.in: Guest P.C. Reviews on Biomarker Studies in Psychiatric and Neurodegenerative Disorders. Springer International, Cham, Switzerland2019: 175-190
- MicroRNAs and exosomes in depression: Potential diagnostic biomarkers.J Cell Biochem. 2018; 119: 3783-3797
- A brain-specific microRNA regulates dendritic spine development.Nature. 2006; 439: 283-289
- MicroRNAs and synaptic plasticity—a mutual relationship.Philos Trans R Soc London B Biol Sci. 2014; 369: 20130515
- Activity-dependent spatially localized miRNA maturation in neuronal dendrites.Science. 2017; 355: 634-637
- MicroRNA functions in animal development and human disease.Development. 2005; 132: 4653-4662
- Role of netrin-1 in the organization and function of the mesocorticolimbic dopamine system.J Psychiatry Neurosci. 2011; 36: 296-310
- A functional screen implicates microRNA-138-dependent regulation of the depalmitoylation enzyme APT1 in dendritic spine morphogenesis.Nat Cell Biol. 2009; 11: 705-716
- Activity-dependent netrin-1 secretion drives synaptic insertion of GluA1-containing AMPA receptors in the hippocampus.Cell Rep. 2018; 25: 168-182.e6
- Neurite-enriched microRNA-218 stimulates translation of the GluA2 subunit and increases excitatory synaptic strength.Mol Neurobiol. 2019; 56: 5701-5714
- Pre- and post-synaptic roles for DCC in memory consolidation in the adult mouse hippocampus.Mol Brain. 2020; 13: 56
- The netrin receptor DCC is required in the pubertal organization of mesocortical dopamine circuitry.J Neurosci. 2011; 31: 8381-8394
- Amphetamine in adolescence disrupts the development of medial prefrontal cortex dopamine connectivity in a dcc-dependent manner.Neuropsychopharmacology. 2015; 40: 1101-1112
- MicroRNA-based therapeutics in central nervous system injuries.J Cereb Blood Flow Metab. 2018; 38: 1125-1148
- Drug target miRNAs: Chances and challenges.Trends Biotechnol. 2014; 32: 578-585
- Intranasal delivery to the central nervous system: Mechanisms and experimental considerations.J Pharm Sci. 2010; 99: 1654-1673
- Intranasal administration of CNS therapeutics to awake mice.J Vis Exp. 2013; 74: 4440
- Intranasal delivery of antipsychotic drugs.Schizophr Res. 2017; 184: 2-13
- The promise of intranasal esketamine as a novel and effective antidepressant.JAMA Psychiatry. 2018; 75: 123-124
- A new rapid-acting antidepressant.Cell. 2020; 181: 7
- A randomized controlled trial of intranasal ketamine in major depressive disorder.Biol Psychiatry. 2014; 76: 970-976
- miR-214-3p targets β-catenin to regulate depressive-like behaviors induced by chronic social defeat stress in mice.Cereb Cortex. 2019; 29: 1509-1519
- Understanding the epigenetic basis of sex differences in depression.J Neurosci Res. 2017; 95: 692-702
- The molecular basis for sex differences in depression susceptibility.Curr Opin Behav Sci. 2018; 23: 1-6
- Sex differences in vulnerability and resilience to stress across the life span.Biol Psychiatry. 2019; 86: 421-432
Article info
Publication history
Published online: October 31, 2020
Accepted:
October 23,
2020
Received in revised form:
September 30,
2020
Received:
June 5,
2020
Identification
Copyright
© 2020 Society of Biological Psychiatry.
