Reduced expression of glucocorticoid-inducible genes GILZ and SGK-1: high IL-6 levels are associated with reduced hippocampal volumes in major depressive disorder
Open accessAbstract
Neuroplasticity may have a core role in the pathophysiology of major depressive disorder (MDD), a concept supported by experimental studies that found that excessive cortisol secretion and/or excessive production of inflammatory cytokines impairs neuronal plasticity and neurogenesis in the hippocampus. The objective of this study was to examine how changes in the glucocorticoid and inflammatory systems may affect hippocampal volumes in MDD. A multimodal approach with structural neuroimaging of hippocampus and amygdala, measurement of peripheral inflammatory proteins interleukin (IL)-6 and C-reactive protein (CRP), glucocorticoid receptor (GR) mRNA expression, and expression of glucocorticoid-inducible genes (glucocorticoid-inducible genes Leucin Zipper (GILZ) and glucocorticoid-inducible kinase-1 (SGK-1)) was used in 40 patients with MDD and 43 healthy controls (HC). Patients with MDD showed smaller hippocampal volumes and increased inflammatory proteins IL-6 and CRP compared with HC. Childhood maltreatment was associated with increased CRP. Patients with MDD, who had less expression of the glucocorticoid-inducible genes GILZ or SGK-1 had smaller hippocampal volumes. Regression analysis showed a strong positive effect of GILZ and SGK-1 mRNA expression, and further inverse effects of IL-6 concentration, on hippocampal volumes. These findings suggest that childhood maltreatment, peripheral inflammatory and glucocorticoid markers and hippocampal volume are interrelated factors in the pathophysiology of MDD. Glucocorticoid-inducible genes GILZ and SGK-1 might be promising candidate markers for hippocampal volume changes relevant for diseases like MDD. Further studies need to explore the possible clinical usefulness of such a blood biomarker, for example, for diagnosis or prediction of therapy response.
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In major depressive disorder, higher peripheral pro-inflammatory cytokines, more inflammation-related gene expression, and less neuroprotective gene expression are associated with greater hippocampal volume loss and medial prefrontal cortex thinning.
“higher levels of peripheral pro-inflammatory cytokines, greater expression of inflammation-related genes, and reduced expression of neuroprotective genes, have all been associated with greater hippocampal volume decline and mPFC thinning in MDD (95–97).”
From The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology (2019) · cites this paper as [95]
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- Authors
- Frodl, T., Carballedo, A., Hughes, M. M., Saleh, K., Fagan, A., Skokauskas, N., McLoughlin, D. M., Meaney, J., O'Keane, V, & Connor, T. J.
- Affiliations
- Trinity College Dublin (IE)
- St. James's Hospital (IE)
- Corresponding author
- Frodl, T
- Venue
- Translational Psychiatry
- Published
- 2012-03-13
- Volume
- 2
- Issue
- 3
- Pages
- e88-e88
- ISSN
- 2158-3188 (ISSN-L)
- PMC
- PMC3309536
- OpenAlex
- W2164860485
- Cited by
- 176
- References
- 45
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 9 · 2023: 7 · 2022: 12 · 2021: 14 · 2020: 15 · 2019: 15 · 2018: 16 · 2017: 10 · 2016: 15 · 2015: 15 · 2014: 16 · 2013: 13 · 2012: 4
- FWCI
- 6.37
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- www.springer.com/tdm (unspecified)
- Locations
- Translational Psychiatry (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Lenus, The Irish Health Repository (Dr Steevens Hospital Library) (submittedVersion)
- Funders
- Health Research Board
- Science Foundation Ireland (SFI/07/SK/B1214C)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- major depressive disorder, hippocampal volume, GILZ, SGK1, interleukin-6, C-reactive protein, child abuse, glucocorticoid receptor, neuroinflammation, glucocorticoid signaling, blood biomarkers, amygdala, neuroplasticity
- MeSH terms
- Serum-Glucocorticoid Regulated Kinases, Adult, Amygdala, C-Reactive Protein, Child, Child Abuse, Major Depressive Disorder, Dominance, Cerebral, Female, Hippocampus, Humans, Male, Middle Aged, Organ Size, Receptors, Glucocorticoid, Reference Values, RNA, Messenger, Statistics as Topic, Transcription Factors, Interleukin-6, Gene Expression, Protein Serine-Threonine Kinases, Immediate-Early Proteins
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