MicroRNA 135 is essential for chronic stress resiliency, antidepressant efficacy, and intact serotonergic activity
Open accessAbstract
The link between dysregulated serotonergic activity and depression and anxiety disorders is well established, yet the molecular mechanisms underlying these psychopathologies are not fully understood. Here, we explore the role of microRNAs in regulating serotonergic (5HT) neuron activity. To this end, we determined the specific microRNA "fingerprint" of 5HT neurons and identified a strong microRNA-target interaction between microRNA 135 (miR135), and both serotonin transporter and serotonin receptor-1a transcripts. Intriguingly, miR135a levels were upregulated after administration of antidepressants. Genetically modified mouse models, expressing higher or lower levels of miR135, demonstrated major alterations in anxiety- and depression-like behaviors, 5HT levels, and behavioral response to antidepressant treatment. Finally, miR135a levels in blood and brain of depressed human patients were significantly lower. The current results suggest a potential role for miR135 as an endogenous antidepressant and provide a venue for potential treatment and insights into the onset, susceptibility, and heterogeneity of stress-related psychopathologies.
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Chronic stress causes dendritic retraction in mPFC, dorsal hippocampus, and dorsomedial striatum but hypertrophy in BLA, vHPC, orbitofrontal cortex, and dorso-lateral striatum and no change in lateral or central subnuclei of the amygdala.
“Chronic stress causes dendritic retraction in mPFC, dorsal hippocampus, and dorsomedial striatum but hypertrophy in the BLA, vHPC, orbitofrontal cortex, and dorso-lateral striatum and no change in the lateral or central subnuclei of the amygdala (3,54,57–61).”
From Chronic Stress Remodels Synapses in an Amygdala Circuit-Specific Manner (2019) · cites this paper as [60]
Depressed individuals and suicide victims showed reduced miR-135a levels in their blood and post-mortem dorsal raphe nucleus, respectively, and blood miR-135a levels in depressed patients increased after antidepressant treatment.
“Importantly, depressed individuals and suicide victims showed reduced miR-135a levels in their blood and post-mortem dorsal raphe nucleus, respectively, and blood miR-135a levels in depressed patients increased after antidepressant treatment.”
From Epigenetic mechanisms of major depression: Targeting neuronal plasticity (2018) · cites this paper as [142]
Environmental stress and antidepressant medications change miRNA expression levels in various brain regions that control mood, including the prefrontal cortex, amygdala, nucleus accumbens, locus coeruleus, and dorsal raphe nucleus.
“Environmental stress and antidepressant medications change miRNA expression levels in various brain regions that control mood, including the PFC, amygdala, nucleus accumbens, locus coeruleus, and dorsal raphe nucleus.”
From Epigenetic mechanisms of major depression: Targeting neuronal plasticity (2018) · cites this paper as [142]
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- Authors
- Issler, O., Haramati, S., Paul, E. D., Maeno, H., Navon, I., Zwang, R., Gil, S., Mayberg, H. S., Dunlop, B. W., Menke, A., Awatramani, R., Binder, E. B., Deneris, E. S., Lowry, C. A., & Chen, A.
- Affiliations
- Max Planck Institute of Psychiatry (DE)
- Weizmann Institute of Science (IL)
- University of Colorado Boulder (US)
- Case Western Reserve University (US)
- Emory University (US)
- Northwestern University (US)
- Corresponding author
- Chen, Alon
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2014-07
- Volume
- 83
- Issue
- 2
- Pages
- 344-360
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W2100746803
- Cited by
- 318
- References
- 82
- Citations by year
- 2026: 6 · 2025: 19 · 2024: 19 · 2023: 21 · 2022: 22 · 2021: 35 · 2020: 26 · 2019: 46 · 2018: 30 · 2017: 32 · 2016: 39 · 2015: 16 · 2014: 6
- FWCI
- 22.52
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Digital Library (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- National Institute of Mental Health (P50MH078028, R01MH062723, R01MH086539)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- chronic stress, stress resilience, depression, anxiety, antidepressant efficacy, serotonin, serotonergic neurons, serotonin transporter, serotonin receptor 1A, miRNA-target interactions, genetically modified mice
- MeSH terms
- Animals, Antidepressive Agents, Anxiety, Behavior, Animal, Brain, Depression, Mice, Transgenic, Serotonin, Social Behavior, Stress, Psychological, MicroRNAs, Receptor, Serotonin, 5-HT1A, Serotonin Plasma Membrane Transport Proteins, Mice, Resilience, Psychological, Serotonergic Neurons
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