The DOI matches its Crossref record; 216 of the 216 references it cites were found in a registry or an index.
Glutamatergic Synaptic Dysregulation in Schizophrenia: Therapeutic Implications
Open accessAbstract
Schizophrenia affects approximately 1% of the population and continues to be associated with poor outcome because of the limited efficacy of and noncompliance with existing antipsychotic medications. An alternative hypothesis invoking the excitatory neurotransmitter, glutamate, arose out of clinical observations that NMDA receptor antagonists, the dissociative anesthetics like ketamine, can replicate in normal individuals the full range of symptoms of schizophrenia including psychosis, negative symptoms, and cognitive impairments. Low dose ketamine can also re-create a number of physiologic abnormalities characteristic of schizophrenia. Postmortem studies have revealed abnormalities in endogenous modulators of NMDA receptors in schizophrenia as well as components of a postsynaptic density where NMDA receptors are localized. Gene association studies have revealed several genes that affect NMDA receptor function whose allelic variants are associated with increased risk for schizophrenia including genes encoding D-amino acid oxidase, its modulator G72, dysbindin, and neuregulin. The parvalbumin-positive, fast-firing GABAergic interneurons that provide recurrent inhibition to cortical-limbic pyramidal neurons seem to be most sensitive to NMDA receptor hypofunction. As a consequence, disinhibition of glutamatergic efferents disrupts cortical processing, causing cognitive impairments and negative symptoms, and drives subcortical dopamine release, resulting in psychosis. Drugs designed to correct the cortical-limbic dysregulated glutamatergic neurotransmission show promise for reducing negative and cognitive symptoms of schizophrenia as well as its positive symptoms.
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“Post-mortem studies of the brain of patients with schizophrenia have revealed lower levels of expression of the obligate NMDAR subunit GRIN1 (glutamate receptor ionotropic, NMDA 1), increases in the expression of the endogenous NMDAR antagonist kynurenate, and a reduction in levels of the NMDAR co-agonist D-serine and the enzyme that catalyses its production, D-serine racemase 10,[16][17][18] .”
From Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis (2016) · cites this paper as [10]
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“As in humans, treatment of adult rodents with NMDAR antagonists triggers acute schizophrenia-related behaviours, including deficits in attention and/ or vigilance, learning and memory and sensory gating, broadly mimicking the symptoms of patients with schizophrenia 10,15,23,24 .”
From Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis (2016) · cites this paper as [10]
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“In supporting of this notion, NMDAR antagonism during an equivalent period in rodents (first 2 post-natal weeks) induces long-lasting behavioural and cognitive disturbances that are relevant to the schizophrenia phenotype and which extend into adolescence and adulthood 10,27 .”
From Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis (2016) · cites this paper as [10]
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Items 201–216 of 216
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Association study of PICK1 rs3952 polymorphism and schizophrenia
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Self-citationDysregulation of glutamate carboxypeptidase II in psychiatric disease
Guilarte, T. R., Hammoud, D. A., McGlothan, J. L., Caffo, B. S., Foss, C. A., Kozikowski, A. P., & Pomper, M. G. (2008) · Schizophrenia Research · doi:10.1016/j.schres.2007.11.013 · Cited by 42
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Self-citationVulnerability to psychosis associated with hallucinogen use
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Early brain wiring: activity-dependent processes
Penn, A. A. (2001) · Schizophrenia Bulletin · doi:10.1093/oxfordjournals.schbul.a006880 · Cited by 37 · cited 1×
“Though the specific biological mechanisms of these insults have not yet been elucidated, the multiple roles of NMDAR-mediated neurotransmission in brain development of preclinical species are widely documented (Shatz 1990; Scheetz and Constantine-Paton 1994; Penn 2001).”
BackgroundGABA Transporters GAT-1 and GAT-3 in the Human Dorsolateral Prefrontal Cortex in Schizophrenia
Schleimer, S. B., Hinton, T., Dixon, G., & Johnston, G. A. R. (2004) · Neuropsychobiology · doi:10.1159/000079975 · Cited by 36
Effects of excitatory amino acids on neuromuscular development in the chick embryo
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Altered NMDA receptor expression in schizophrenia
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Glial metabolites of tryptophan and excitotoxicity: Coming unglued
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Self-citationCardno, A. G., & Gottesman, I. I. (2000) · American Journal of Medical Genetics · doi:10.1002/(sici)1096-8628(200021)97:1
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Brisch, R., Saniotis, A., Wolf, R. J., Bielau, H., Bernstein, H., Steiner, J. H., Bogerts, B., Braun, A. K., Jankowski, Z., Kumaritlake, J., et al. (2014) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2014.00047 · Cited by 575
The touchscreen operant platform for testing learning and memory in rats and mice
Horner, A. E., Heath, C. J., Hvoslef‐Eide, M., Kent, B. A., Kim, C. H., Nilsson, S. R. O., Alsiö, J., Oomen, C. A., Holmes, A., Saksida, L. M., et al. (2013) · Nature Protocols · doi:10.1038/nprot.2013.122 · Cited by 412
Millan, M. J., Fone, K. C. F., Steckler, T., & Horan, W. P. (2014) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2014.03.008 · Cited by 376
Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis
Hardingham, G. E., & Do, K. Q. (2016) · Nature Reviews Neuroscience · doi:10.1038/nrn.2015.19 · Cited by 304
Reviewing the ketamine model for schizophrenia
Frohlich, J., & Van Horn, J. D. (2014) · Journal of Psychopharmacology · doi:10.1177/0269881113512909 · Cited by 303
Metadata
- Authors
- Coyle, J. T., Basu, A., Benneyworth, M., Balu, D., & Konopaske, G.
- Affiliations
- Harvard University (US)
- Corresponding author
- Coyle, Joseph T.
- Venue
- Handbook of Experimental Pharmacology
- Publisher
- Springer Berlin Heidelberg
- Published
- 2012
- Issue
- 213
- Pages
- 267-295
- ISSN
- 0171-2004 (ISSN-L)
- 1865-0325
- PMC
- PMC4817347
- OpenAlex
- W1872072116
- Cited by
- 180
- References
- 216
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 6 · 2023: 4 · 2022: 13 · 2021: 19 · 2020: 10 · 2019: 9 · 2018: 10 · 2017: 11 · 2016: 11 · 2015: 21 · 2014: 25 · 2013: 22 · 2012: 4
- FWCI
- 81.63
- Type
- book chapter
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Handbook of experimental pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Public Health Service
- National Institute of Mental Health (P50MH060450, R01 MH51290, R01MH051290, F32MH090697, P50MH06045)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- schizophrenia, NMDA receptor hypofunction, ketamine, dissociative anesthetics, postsynaptic density, D-amino acid oxidase, G72, dysbindin, neuregulin, parvalbumin interneurons, cognitive impairment, negative symptoms, psychosis, dopamine release, glutamatergic neurotransmission
- MeSH terms
- Animals, Cognition, gamma-Aminobutyric Acid, Humans, Ketamine, Synaptic Transmission, Schizophrenia, Synapses, Receptors, N-Methyl-D-Aspartate, Glutamic Acid
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