Prefrontal changes in the glutamate-glutamine cycle and neuronal/glial glutamate transporters in depression with and without suicide
Open accessAbstract
There are indications for changes in glutamate metabolism in relation to depression or suicide. The glutamate-glutamine cycle and neuronal/glial glutamate transporters mediate the uptake of the glutamate and glutamine. The expression of various components of the glutamate-glutamine cycle and the neuronal/glial glutamate transporters was determined by qPCR in postmortem prefrontal cortex. The anterior cingulate cortex (ACC) and the dorsolateral prefrontal cortex (DLPFC) were selected from young MDD patients who had committed suicide (MDD-S; n = 17), from MDD patients who died of non-suicide related causes (MDD-NS; n = 7) and from matched control subjects (n = 12). We also compared elderly depressed patients who had not committed suicide (n = 14) with matched control subjects (n = 22). We found that neuronal located components (EAAT3, EAAT4, ASCT1, SNAT1, SNAT2) of the glutamate-glutamine cycle were increased in the ACC while the astroglia located components (EAAT1, EAAT2, GLUL) were decreased in the DLPFC of MDD-S patients. In contrast, most of the components in the cycle were increased in the DLPFC of MDD-NS patients. In conclusion, the glutamate-glutamine cycle - and thus glutamine transmission - is differentially affected in depressed suicide patients and depressed non-suicide patients in an area specific way.
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“While astrocyte abnormalities have previously been reported in BPD and MDD patients (Zhao et al., 2016; Wang et al., 2017; Giridharan et al., 2019), the changes in their size, density, area fraction as well as the gene expression of their specific markers in cortical gray matter of ACC and DLPFC remains inconclusive.”
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“Moreover, we have observed changes in the expression levels of neurotransmitter-related and stress-related molecules (11, 33, 57, 58) in these brain areas in mood disorders.”
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Differentially methylated regions in bipolar disorder and suicide
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EAAT2 as a Research Target in Bipolar Disorder and Unipolar Depression: A Systematic Review
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Caudothalamic dysfunction in drug-free suicidally depressed patients: an MEG study
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“Our series of studies have found expression changes for a number of genes related to the production/release of glutamate, GABA, stress hormone, retinoid, and nitric oxide (NO) in DLPFC and/or ACC of mood disorder patients (Gao et al. 2013; Qi et al. 2013, 2015; ; Zhao et al. 2015, 2016).”
BackgroundSelf-citationSex differences in the transcription of glutamate transporters in major depression and suicide.
Powers, B., Joyce, C., Kleinman, J. E., Hyde, T. M., Ajilore, O., Leow, A., & Sodhi, M. (2020) · Journal of Affective Disorders · doi:10.1016/j.jad.2020.07.055 · Cited by 21 · see citing works
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“In the search for candidate genes involved in suicide and attempted suicide, previous studies have examined genes implicated in neurotransmitter systems, including the GABAergic, glutamatergic, serotonergic, noradrenergic, and dopaminergic systems [9,10].”
BackgroundKetamine Alters Functional Plasticity of Astroglia: An Implication for Antidepressant Effect
Stenovec, M. (2021) · Life · doi:10.3390/life11060573 · Cited by 17 · see citing works
Glial Markers of Suicidal Behavior in the Human Brain—A Systematic Review of Postmortem Studies
Yamamoto, M., Sakai, M., Yu, Z., Nakanishi, M., & Yoshii, H. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25115750 · Cited by 16 · see citing works
“Furthermore, literature not in our searched target indicated that astroglia located SLC1A3 and GLUL transcripts decreased in the DLPFC of suicidal MMD patients [69].”
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Proteomic profiling of postmortem prefrontal cortex tissue of suicide completers
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Suicide Is a Confounder in Postmortem Studies on Depression
Zhao, J., Lucassen, P. J., & Swaab, D. F. (2019) · Biological Psychiatry · doi:10.1016/j.biopsych.2019.04.015 · Cited by 15 · see citing works
Self-citationZeng, Z., Dong, Y., Zou, L., Xu, D., Luo, X., Chu, T., Wang, J., Ren, Q., Liu, Q., & Li, X. (2023) · Journal of Magnetic Resonance Imaging · doi:10.1002/jmri.28651 · Cited by 14 · see citing works
“28 In this cycle, glutamate is released by glutamatergic synapses and then taken up into surrounding astrocytes, transformed into glutamine and released into the extracellular space, fi nally taken up into neurons and transformed back to glutamate.”
Neuroprotective astroglial response to neural damage and its relevance to affective disorders
Miguel-Hidalgo, J. J. (2023) · Exploration of Neuroprotective Therapy · doi:10.37349/ent.2023.00054 · Cited by 14 · see citing works
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“These fi ndings have been reinforced by other reports [20 – 24].”
Astrocytes and neuropsychiatric symptoms in neurodegenerative diseases: Exploring the missing links
Haim, L. B., & Escartin, C. (2021) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2021.09.002 · Cited by 13 · see citing works
Fullana, M. N., Paz, V., Artigas, F., & Bortolozzi, A. A. (2021) · Revista de Psiquiatría y Salud Mental · doi:10.1016/j.rpsm.2021.09.002 · Cited by 11 · see citing works
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Calabrese, L. V. (2019) · International Journal of Psychiatry Research · doi:10.33425/2641-4317.1033 · Cited by 11 · see citing works
“Although the genesis of suicidal ideation and behaviors in any one individual is complex and multifactorial, it has been suggested that dysregulation in glutamate neurotransmission may underlie suicidal ideation [23-25], and to date, ketamine is the most widely studied glutamate modulator for the treatment of psychiat…”
BackgroundAstrocytes in Neuropsychiatric Disorders: A Review of Postmortem Evidence
Zhang, X., Alnafisah, R. S., Hamoud, A.-R. A., Shukla, R., McCullumsmith, R. E., & O'Donovan, S. M. (2021) · Advances in neurobiology · doi:10.1007/978-3-030-77375-5_8 · Cited by 11 · see citing works
Wei, Q., Zhang, H., Guan, H., Song, X., & Zhou, H. (2024) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2024.101159 · Cited by 13 · see citing works
Proteomic evidence of depression-associated astrocytic dysfunction in the human male olfactory bulb
Rahimian, R., Perlman, K., Fakhfouri, G., Mpai, R., Richard, V. R., Hercher, C., Penney, L., Davoli, M. A., Nagy, C., Zahedi, R. P., et al. (2024) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2024.08.016 · Cited by 8 · see citing works
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Air pollution exposure increases ABCB1 and ASCT1 transporter levels in mouse cortex
Puris, E., Saveleva, L., Górová, V., Vartiainen, P., Kortelainen, M., Lamberg, H., Sippula, O., Malm, T., Jalava, P., Auriola, S. O. K., et al. (2022) · Environmental Toxicology and Pharmacology · doi:10.1016/j.etap.2022.104003 · Cited by 8 · see citing works
Physical Activity and Depression in Breast Cancer Patients: Mechanisms and Therapeutic Potential
Li, A., Zheng, X., Liu, D., Huang, R., Ge, H., Cheng, L. J., Zhang, M., & Cheng, H. (2025) · Current Oncology · doi:10.3390/curroncol32020077 · Cited by 7 · see citing works
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Metabonomic Profile and Signaling Pathway Prediction of Depression-Associated Suicidal Behavior
Liu, S. (2020) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2020.00269 · Cited by 6 · see citing works
“They observed that the glutate-glutamine cycle was significantly changed in depressed suicide patients (65).”
BackgroundRegulation of SLC1A4 and SLC1A5 in Prostate Cancer—Response
White, M. A., & Frigo, D. E. (2018) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-18-0240 · Cited by 6 · see citing works
“3B), and the published role of SLC1A4 in glutamine/glutamate cycling (4, 5), we think we cannot rule out the possibility that SLC1A4 could transport glutamine under some contexts.”
BackgroundFullana, M. N., Paz, V., Artigas, F., & Bortolozzi, A. A. (2022) · Revista de Psiquiatría y Salud Mental (English Edition) · doi:10.1016/j.rpsmen.2022.06.008 · Cited by 5 · see citing works
Talty, C.-E., Murphy, S. F., & VandeVord, P. (2024) · Neuroscience · doi:10.1016/j.neuroscience.2024.09.039 · Cited by 5 · see citing works
“In patients diagnosed with MDD, decreases in astrocytic glutamate transporters GLT-1 and GLAST have been reported in brain regions associated with depression, specifically the prefrontal cortex (Choudary et al., 2005; Zhao et al., 2016) and hippocampus (Medina et al., 2013; Medina et al., 2016).”
Roddy, D. W., Kelly, J. R., Drago, T. J., Raajakesary, K., Haines, M., & O’Hanlon, E. (2022) · Neuromethods · doi:10.1007/978-1-0716-2083-0_13 · Cited by 3 · see citing works
Umbelliferon, Glutamat Eksitotoksisitesine Karşı Primer Kortikal Nöron Hücrelerini Korur mu?
Demirkaya, A. K., Gündoğdu, G., Karakaya, S., Tascı, S. Y., Nalcı, K. A., & Hacımüftüoğlu, A. (2021) · Kafkas Universitesi Veteriner Fakultesi Dergisi · doi:10.9775/kvfd.2021.25439 · Cited by 3 · see citing works
“Glutamate concentration in the synaptic cleft is increased by synaptic activity, but extracellular glutamate concentration is protected by glutamate uptake by glutamate transporter [9,10].”
Babber, A., & Sharma, A. (2024) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s491176 · Cited by 2 · see citing works
Martínez-Pinteño, A., Olivares-Berjaga, D., Rodríguez, N., Mena, J.-I., Prohens, L., Mas, S., Morén, C., Parellada, E., & Gassó, P. (2025) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2025.118639 · Cited by 2 · see citing works
Suicidality and Cannabidiol: Opportunities and Challenges
Zadeh, E. M., & GALYNKER, I. I. (2020) · Current Neuropharmacology · doi:10.2174/1570159x18666201015160417 · Cited by 2 · see citing works
“the anterior cingulate cortex (ACC) [21-23].”
InfluentialPowers, B., Kleinman, J. E., Hyde, T. M., Ajilore, O., Leow, A., & Sodhi, M. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/596403 · Cited by 2 · see citing works
“Other studies of mixed-sex cohorts have reported decreased expression of EAAT1 and EAAT2 in the DLPFC in MDD-S(58), and in suicides with schizophrenia (61) with smaller effects in males.”
BackgroundZhang, X., Wolfinger, A., Shukla, R., Lundh, A., Wu, X., Abel, M. E., McCullumsmith, R. E., & O'Donovan, S. M. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.09.22.461367 · Cited by 2 · see citing works
“For example, there is evidence of both increased [4-8] and decreased [7, 9-19] astrocyte marker expression, increased [6, 10] and decreased [20-26] astrocyte cell counts, changes in astrocyte morphology [7, 27-29], as well as no significant changes in astrocyte expression [27, 30-35] in disorders like schizophrenia an…”
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Self-citationBiological theories of suicidal behaviour
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Prefrontal gene expression changes in mood disorders and suicide
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A narrative review of astrocytes and suicide in psychiatric disorders
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Biological theories of suicidal behaviour
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“[41] These biochemical and gene expression studies provide additional insights into the neural basis of suicide.”
Talty, C.-E., Wypyski, M. S., Murphy, S. F., & VandeVord, P. J. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27062670
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Role of astrocytes in the development and progression of major depressive disorder
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Glutamine metabolism in health and disease
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“410 It has been found that the expression of system A transporters (SLC38A1/2), system N transporters (SLC38A3/5), and GLT1 is altered in the brains of depressed patients.”
Self-citation
- Authors
- Zhao, J., Verwer, R. W. H., van Wamelen, D. J., Qi, X.-R., Gao, S.-F., Lucassen, P. J., & Swaab, D. F.
- Affiliations
- Netherlands Institute for Neuroscience (NL)
- University of Amsterdam (NL)
- Corresponding author
- Swaab, D.F.
- Venue
- Journal of Psychiatric Research
- Publisher
- Elsevier BV
- Published
- 2016-11
- Volume
- 82
- Pages
- 8-15
- ISSN
- 0022-3956 (ISSN-L)
- OpenAlex
- W2465845564
- Cited by
- 83
- References
- 60
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 8 · 2023: 8 · 2022: 6 · 2021: 12 · 2020: 9 · 2019: 14 · 2018: 11 · 2017: 6
- FWCI
- 8.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Psychiatric Research (publishedVersion)
- PubMed (publishedVersion)
- UvA-DARE (University of Amsterdam) (publishedVersion, other-oa)
- KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- UvA-DARE (University of Amsterdam) (submittedVersion, other-oa)
- Research Portal (King's College London) (submittedVersion)
- KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- Koninklijke Nederlandse Akademie van Wetenschappen (10CDP037)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- depression, suicide, glutamate-glutamine cycle, glutamate transporters, prefrontal cortex, anterior cingulate cortex, dorsolateral prefrontal cortex, EAAT3, EAAT4, GLAST, GLT-1, glutamine synthetase, SNAT1, SNAT2, ASCT1, glutamate metabolism, postmortem brain
- MeSH terms
- Aged, Aged, 80 and over, Depression, Female, Glutamine, Humans, Male, Middle Aged, Netherlands, Postmortem Changes, Psychiatric Status Rating Scales, Suicide, Prefrontal Cortex, Glutamic Acid, Amino Acid Transport System X-AG
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