Cellular and molecular basis for stress-induced depression

Mol Psychiatry. 2017 Oct;22(10):1440-1447. doi: 10.1038/mp.2016.118. Epub 2016 Jul 26.

Abstract

Chronic stress has a crucial role in the development of psychiatric diseases, such as anxiety and depression. Dysfunction of the medial prefrontal cortex (mPFC) has been linked to the cognitive and emotional deficits induced by stress. However, little is known about the molecular and cellular determinants in mPFC for stress-associated mental disorders. Here we show that chronic restraint stress induces the selective loss of p11 (also known as annexin II light chain, S100A10), a multifunctional protein binding to 5-HT receptors, in layer II/III neurons of the prelimbic cortex (PrL), as well as depression-like behaviors, both of which are reversed by selective serotonin reuptake inhibitors (SSRIs) and the tricyclic class of antidepressant (TCA) agents. In layer II/III of the PrL, p11 is highly concentrated in dopamine D2 receptor-expressing (D2+) glutamatergic neurons. Viral expression of p11 in D2+ PrL neurons alleviates the depression-like behaviors exhibited by genetically manipulated mice with D2+ neuron-specific or global deletion of p11. In stressed animals, overexpression of p11 in D2+ PrL neurons rescues depression-like behaviors by restoring glutamatergic transmission. Our results have identified p11 as a key molecule in a specific cell type that regulates stress-induced depression, which provides a framework for the development of new strategies to treat stress-associated mental illnesses.

Publication types

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

MeSH terms

  • Animals
  • Annexin A2 / genetics
  • Annexin A2 / metabolism*
  • Annexin A2 / physiology
  • Anxiety Disorders / metabolism
  • Anxiety Disorders / physiopathology
  • Chronic Disease
  • Depression / metabolism*
  • Depression / physiopathology
  • Depressive Disorder / metabolism
  • Depressive Disorder / physiopathology
  • Emotions / drug effects
  • Humans
  • Mice
  • Mice, Transgenic
  • Neurons / metabolism
  • Prefrontal Cortex / metabolism
  • Prefrontal Cortex / physiopathology
  • Receptors, Dopamine D2 / metabolism
  • Receptors, Serotonin / metabolism
  • S100 Proteins / genetics
  • S100 Proteins / metabolism*
  • S100 Proteins / physiology
  • Serotonin Uptake Inhibitors / pharmacology
  • Stress, Psychological / metabolism*
  • Stress, Psychological / physiopathology

Substances

  • Annexin A2
  • DRD2 protein, human
  • Receptors, Dopamine D2
  • Receptors, Serotonin
  • S100 Proteins
  • S100 calcium binding protein A10
  • Serotonin Uptake Inhibitors