GPCR signaling: role in mediating the effects of early adversity in psychiatric disorders

FEBS J. 2021 Apr;288(8):2602-2621. doi: 10.1111/febs.15738. Epub 2021 Feb 16.


Early adversity is a key risk factor for the development of several psychiatric disorders, including anxiety and depression. During early life, neurocircuits that regulate emotionality undergo substantial structural remodeling and functional maturation, and are thus particularly susceptible to modification by environmental experience. Preclinical evidence indicates that early stress enhances adult anxio-depressive behaviors. A commonality noted across diverse early stress models is life-long alterations in neuroendocrine stress responses and monoaminergic neurotransmission in key limbic circuits. Dysregulation of G protein-coupled receptor (GPCR) signaling is noted across multiple early stress models and is hypothesized to be an important player in the programming of aberrant emotionality. This raises the possibility that disruption of GPCR signaling in key limbic regions during critical temporal windows could establish a substrate for enhanced risk of adult psychopathology. Here, we review literature, predominantly from preclinical models, which supports the building hypothesis that a disruption of GPCR signaling could play a central role in programming persistent molecular, cellular, functional, and behavioral changes as a consequence of early adversity.

Keywords: 5-HT1A receptor; 5-HT2A receptor; anxiety; depression; early stress; maternal separation; monoamine; serotonin.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Anxiety / genetics*
  • Anxiety / pathology
  • Humans
  • Mental Disorders / genetics*
  • Mental Disorders / pathology
  • Receptors, G-Protein-Coupled / genetics*
  • Serotonin / genetics
  • Stress, Psychological / genetics*
  • Synaptic Transmission / genetics


  • Receptors, G-Protein-Coupled
  • Serotonin