MicroRNA 135 Is Essential for Chronic Stress Resiliency, Antidepressant Efficacy, and Intact Serotonergic Activity

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...

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Bibliographic Details
Published in:	Neuron (Cambridge, Mass.) Vol. 83; no. 2; pp. 344 - 360
Main Authors:	Issler, Orna, Haramati, Sharon, Paul, Evan D., Maeno, Hiroshi, Navon, Inbal, Zwang, Rayya, Gil, Shosh, Mayberg, Helen S., Dunlop, Boadie W., Menke, Andreas, Awatramani, Rajeshwar, Binder, Elisabeth B., Deneris, Evan S., Lowry, Christopher A., Chen, Alon
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 16-07-2014 Elsevier Limited
Subjects:	Animals Antidepressants Antidepressive Agents - pharmacology Antidepressive Agents - therapeutic use Anxiety Anxiety - genetics Anxiety - metabolism Behavior modification Behavior, Animal - drug effects Behavior, Animal - physiology Bioinformatics Brain - drug effects Brain - metabolism Brain research Depression - drug therapy Depression - genetics Depression - metabolism Emotional disorders Enzymes Gene expression Grants Hypotheses Mice Mice, Transgenic MicroRNAs MicroRNAs - genetics MicroRNAs - metabolism Neurons Receptor, Serotonin, 5-HT1A - genetics Receptor, Serotonin, 5-HT1A - metabolism Resilience, Psychological Rodents Serotonergic Neurons - drug effects Serotonergic Neurons - metabolism Serotonin - metabolism Serotonin Plasma Membrane Transport Proteins - genetics Serotonin Plasma Membrane Transport Proteins - metabolism Social Behavior Stress, Psychological - genetics Stress, Psychological - metabolism Studies
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Summary:	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. •miRs “fingerprint” of 5HT neurons position miR135 as potent regulator of 5HT system•miR135a levels are upregulated following 5HT-linked antidepressants treatment•miR135 levels in vivo influence behavior, 5HT levels, and antidepressant treatment•Lower levels of miR135a in blood and brain of depressed human patients Issler et al. identify microRNA135 as potent regulator of serotonergic activity known to be associated with depression and anxiety disorders and suggest a role for miR135 as an endogenous antidepressant and provide a venue for potential treatment and insights into stress-related psychopathologies.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	0896-6273 1097-4199
DOI:	10.1016/j.neuron.2014.05.042