Higher Levels of Pro-inflammatory Cytokines Are Associated With Higher Levels of Glutamate in the Anterior Cingulate Cortex in Depressed Adolescents
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Animal models of stress and related conditions, including depression, have shown that elevated peripheral levels of inflammatory cytokines have downstream consequences on glutamate (Glu) in the brain. Although studies in human adults with depression have reported evidence of higher inflammation but lower Glu in the anterior cingulate cortex (ACC), the extent to which peripheral inflammation contributes to glutamatergic abnormalities in adolescents with depression is not well-understood. It is also unclear whether antioxidants, such as ascorbate (Asc), may buffer against the effects of inflammation on Glu metabolism. Fifty-five depressed adolescents were recruited in the present cross-sectional study and provided blood samples, from which we assayed pro-inflammatory cytokines, and underwent a short-TE proton magnetic spectroscopy scan at 3T, from which we estimated Glu and Asc in the dorsal ACC. In the 31 adolescents with usable cytokine and Glu data, we found that IL-6 was significantly positively associated with dorsal ACC Glu (β = 0.466 ± 0.199, p = 0.029). Of the 16 participants who had usable Asc data, we found that at higher levels of dorsal ACC Asc, there was a negative association between IL-6 and Glu (interaction effect: β = −0.906 ± 0.433, p = 0.034). Importantly, these results remained significant when controlling for age, gender, percentage of gray matter in the dorsal ACC voxel, BMI, and medication (antidepressant and anti-inflammatory) usage. While preliminary, our results underscore the importance of examining both immune and neural contributors to depression and highlight the potential role of anti-inflammatory compounds in mitigating the adverse effects of inflammation (e.g., glutamatergic neuroexcitotoxicity). Future studies that experimentally manipulate levels of inflammation, and of ascorbate, and that characterize these effects on cortical glutamate concentrations and subsequent behavior in animals and in humans are needed.
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Glutamate and its receptors are associated with many neuropsychiatric illnesses, including depression.
“Glutamate and its receptors are associated with many neuropsychiatric illnesses, including depression.275,276”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [276]
The Introduction (page not provided) describes depression-related alterations in glutamate and mentions glutamatergic NMDA receptors in a proposed mechanism. It does not establish that glutamate and its receptors are associated with many neuropsychiatric illnesses; its discussion is focused on depression. (LLM, conf=0.87)
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- [51]Gu M Hurd RE Spielman DM. Quantification of Glutathione and Asocrbate in the human Brain Using Short-TE PRESS. International Society of Magnetic Resonance in Medication (2019). Available online at: https://index.mirasmart.com/ISMRM2019/PDFfiles/2230.html (accessed February 01, 2021).
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“275,276 277 – 283 The monoamine oxidase A (MAO-A) enzyme modulates monoamine neurotransmitter levels. miR-142, miR-34a, and miR-34c indirectly regulate MAO-A, potentially impacting monoamine neurotrans-mitters.”
Background
- Authors
- Ho, T. C., Teresi, G. I., Segarra, J. R., Ojha, A., Walker, J. C., Gu, M., Spielman, D. M., Sacchet, M. D., Jiang, F., Rosenberg-Hasson, Y., Maecker, H., & Gotlib, I. H.
- Affiliations
- University of California, San Francisco (US)
- Stanford University (US)
- University of Pittsburgh (US)
- Harvard University (US)
- Corresponding author
- Ho, Tiffany C.
- ORCID
- Venue
- Frontiers in Psychiatry
- Publisher
- Frontiers Media SA
- Published
- 2021-04-15
- Volume
- 12
- Pages
- 642976-642976
- ISSN
- 1664-0640 (ISSN-L)
- PMC
- PMC8081972
- OpenAlex
- W3156516358
- Cited by
- 32
- References
- 60
- Citations by year
- 2025: 4 · 2024: 9 · 2023: 9 · 2022: 7 · 2021: 3
- FWCI
- 2.32
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Psychiatry (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- National Institute of Mental Health (K01MH117442, R37MH101495)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- adolescent depression, inflammatory cytokines, glutamate, anterior cingulate cortex, interleukin-6, vitamin C, peripheral inflammation, neuroinflammation, 1H NMR
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