Mind the gap: glucocorticoids modulate hippocampal glutamate tone underlying individual differences in stress susceptibility

Mol Psychiatry. 2015 Jun;20(6):755-63. doi: 10.1038/mp.2014.96. Epub 2014 Sep 2.


Why do some individuals succumb to stress and develop debilitating psychiatric disorders, whereas others adapt well in the face of adversity? There is a gap in understanding the neural bases of individual differences in the responses to environmental factors on brain development and functions. Here, using a novel approach for screening an inbred population of laboratory animals, we identified two subpopulations of mice: susceptible mice that show mood-related abnormalities compared with resilient mice, which cope better with stress. This approach combined with molecular and behavioral analyses, led us to recognize, in hippocampus, presynaptic mGlu2 receptors, which inhibit glutamate release, as a stress-sensitive marker of individual differences to stress-induced mood disorders. Indeed, genetic mGlu2 deletion in mice results in a more severe susceptibility to stress, mimicking the susceptible mouse sub-population. Furthermore, we describe an underlying mechanism by which glucocorticoids, acting via mineralocorticoid receptors (MRs), decrease resilience to stress via downregulation of mGlu2 receptors. We also provide a mechanistic link between MRs and an epigenetic control of the glutamatergic synapse that underlies susceptibility to stressful experiences. The approach and the epigenetic allostasis concept introduced here serve as a model for identifying individual differences based upon biomarkers and underlying mechanisms and also provide molecular features that may be useful in translation to human behavior and psychopathology.

Publication types

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

MeSH terms

  • Animals
  • Disease Models, Animal
  • Disease Susceptibility*
  • Food Preferences / drug effects
  • Glucocorticoids / pharmacology*
  • Glutamic Acid / metabolism*
  • Hippocampus / drug effects*
  • Hippocampus / metabolism*
  • Immobility Response, Tonic / drug effects
  • Individuality*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mifepristone
  • Receptors, Metabotropic Glutamate / deficiency
  • Receptors, Metabotropic Glutamate / genetics
  • Receptors, Mineralocorticoid / metabolism
  • Stress, Psychological / drug therapy
  • Stress, Psychological / genetics
  • Sucrose / administration & dosage
  • Sweetening Agents / administration & dosage


  • Glucocorticoids
  • Receptors, Metabotropic Glutamate
  • Receptors, Mineralocorticoid
  • Sweetening Agents
  • metabotropic glutamate receptor 2
  • Mifepristone
  • Glutamic Acid
  • Sucrose