The Role of the Tripartite Glutamatergic Synapse in the Pathophysiology and Therapeutics of Mood Disorders
Open accessAbstract
Bipolar disorder and major depressive disorder are common, chronic, and recurrent mood disorders that affect the lives of millions of individuals worldwide. Growing evidence suggests that glutamatergic system dysfunction is directly involved in mood disorders. This article describes the role of the “tripartite glutamatergic synapse,” comprising presynaptic and postsynaptic neurons and glial cells, in the pathophysiology and therapeutics of mood disorders. Glutamatergic neurons and glia directly control synaptic and extrasynaptic glutamate levels/ release through integrative effects that target glutamate excitatory amino acid transporters, postsynaptic density proteins, ionotropic receptors (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid [AMPA], N-methyl-D-aspartate [NMDA], and kainate), and metabotropic receptors. This article also explores the glutamatergic modulators riluzole and ketamine, which are considered valuable proof-of-concept agents for developing the next generation of antidepressants and mood stabilizers. In therapeutically relevant paradigms, ketamine preferentially targets postsynaptic AMPA/NMDA receptors, and riluzole preferentially targets presynaptic voltage-operated channels and glia.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Metabotropic glutamate receptors have repeatedly been implicated in the pathophysiology of depression, and mGluRs2/3 are known to mediate levels of glutamate and synaptic plasticity.
“Metabotropic glutamate receptors (mGluRs) have repeatedly been implicated in the pathophysiology of depression, and mGluRs2/3 are known to mediate levels of glutamate and synaptic plasticity [189]”
From Ketamine in neuropsychiatric disorders: an update (2024) · cites this paper as [189]
Section II.E links mGluRs to depression through animal-model findings, but says data linking mGluR dysfunction to mood disorders are sparse; this qualifies the claim that they have repeatedly been implicated. The Introduction says metabotropic receptors modulate synaptic plasticity, but our copy does not establish specifically that mGluR2/3 mediate glutamate levels and synaptic plasticity. Page numbers were not available in the indexed passages. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 153 · Cited by 171
- Authors
- Machado-Vieira, R., Manji, H. K., & Zarate, C. A.
- Affiliations
- From the Experimental Therapeutics, Mood and Anxiety Disorders Research Program, NIMH-NIH, Bethesda, Maryland
- Johnson and Johnson Pharmaceutical Research and Development, Titusville, New Jersey
- National Institutes of Health (US)
- Venue
- The Neuroscientist
- Publisher
- SAGE Publications
- Published
- 2009-05-26
- Volume
- 15
- Issue
- 5
- Pages
- 525-539
- ISSN
- 1073-8584 (ISSN-L)
- 1089-4098
- PMC
- PMC2762009
- OpenAlex
- W2171126911
- Cited by
- 171
- References
- 153
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 1 · 2023: 2 · 2022: 7 · 2021: 29 · 2020: 4 · 2019: 5 · 2018: 4 · 2017: 8 · 2016: 13 · 2015: 16 · 2014: 13 · 2013: 10 · 2012: 17
- FWCI
- 1.76
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Neuroscientist (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (Z01MH002828, Z01MH002857)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Keywords
- tripartite synapse, glutamatergic synapses, mood disorders, bipolar disorder, major depressive disorder, glial cells, extrasynaptic glutamate, postsynaptic density proteins, AMPA receptors, NMDA receptor, kainate receptors, metabotropic glutamate receptors, riluzole, ketamine, antidepressants, mood stabilizers
- MeSH terms
- Animals, Brain, Humans, Ketamine, Neuroglia, Synapses, Receptors, Glutamate, Excitatory Amino Acid Antagonists, Glutamic Acid, Riluzole, Mood Disorders
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
