Mind the gap: glucocorticoids modulate hippocampal glutamate tone underlying individual differences in stress susceptibility
Open accessAbstract
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.
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The stratification approach followed is in line with an emerging trend in the literature, taking into account individual differences in behavioral outcomes when examining underlying neurobiology.
“We should briefly note that the stratification approach that we have followed is in line with an emerging trend in the literature, taking into account individual differences in behavioral outcomes when examining underlying neurobiology36,39–44.”
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- Authors
- Nasca, C., Bigio, B., Zelli, D., Nicoletti, F., & McEwen, B. S.
- Affiliations
- Rockefeller University (US)
- Istituto Neurologico Mediterraneo (IT)
- Corresponding author
- Nasca, C
- McEwen, B S
- Venue
- Molecular Psychiatry
- Published
- 2014-09-02
- Volume
- 20
- Issue
- 6
- Pages
- 755-763
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC4366364
- OpenAlex
- W1998658215
- Cited by
- 194
- References
- 44
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 21 · 2023: 11 · 2022: 13 · 2021: 20 · 2020: 19 · 2019: 23 · 2018: 24 · 2017: 13 · 2016: 22 · 2015: 10 · 2014: 2
- FWCI
- 7.69
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Funders
- American Foundation for Suicide Prevention
- Hope for Depression Research Foundation
- National Institutes of Health
- National Institute of Mental Health (R01 MH41256, R01MH041256)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- stress vulnerability, individual differences, glucocorticoids, mineralocorticoid receptor, mGlu2 receptor, hippocampus, glutamate release, stress resilience, mood disorders, glutamatergic synapses, inbred mouse strains, biomarkers
- MeSH terms
- Animals, Disease Models, Animal, Disease Susceptibility, Food Preferences, Glucocorticoids, Hippocampus, Individuality, Mice, Inbred C57BL, Stress, Psychological, Sucrose, Sweetening Agents, Mifepristone, Receptors, Metabotropic Glutamate, Receptors, Mineralocorticoid, Mice, Knockout, Glutamic Acid, Immobility Response, Tonic, Mice
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