MicroRNA 135 is essential for chronic stress resiliency, antidepressant efficacy, and intact serotonergic activity

Neuron. 2014 Jul 16;83(2):344-360. doi: 10.1016/j.neuron.2014.05.042. Epub 2014 Jun 19.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology
  • Antidepressive Agents / therapeutic use*
  • Anxiety / genetics
  • Anxiety / metabolism
  • Behavior, Animal / drug effects
  • Behavior, Animal / physiology
  • Brain / drug effects*
  • Brain / metabolism
  • Depression / drug therapy*
  • Depression / genetics
  • Depression / metabolism
  • Mice
  • Mice, Transgenic
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Receptor, Serotonin, 5-HT1A / genetics
  • Receptor, Serotonin, 5-HT1A / metabolism
  • Resilience, Psychological*
  • 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


  • Antidepressive Agents
  • MicroRNAs
  • Mirn135 microRNA, mouse
  • Serotonin Plasma Membrane Transport Proteins
  • Receptor, Serotonin, 5-HT1A
  • Serotonin