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Cognitive Dysfunction in Schizophrenia: Convergence of γ-Aminobutyric Acid and Glutamate Alterations
Abstract
Impairments in certain cognitive functions mediated by the dorsolateral prefrontal cortex, such as working memory, are core features of schizophrenia. Convergent findings suggest that these disturbances are associated with alterations in markers of inhibitory gamma-aminobutyric acid and excitatory glutamate neurotransmission in the dorsolateral prefrontal cortex. Specifically, reduced gamma-aminobutyric acid synthesis is present in the subpopulation of gamma-aminobutyric acid neurons that express the calcium-binding protein parvalbumin. Despite presynaptic and postsynaptic compensatory responses, the resulting impaired inhibitory regulation of pyramidal neurons contributes to a reduction in the synchronized neuronal activity that is required for working memory function. Several lines of evidence suggest that these changes may be either secondary to or exacerbated by impaired signaling via the N-methyl-d-aspartate class of glutamate receptors. These findings suggest specific targets for therapeutic interventions to improve cognitive function in individuals with schizophrenia.
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“Diminished activation of NMDA-receptors results in insufficient excitatory activity, disrupting the monitoring function of GABAergic inhibitory neurons.”
From Glutamate in Schizophrenia: A Focused Review and Meta-Analysis of 1H-MRS Studies (2013) · cites this paper as [80]
In the citing paper
“In response, these inhibitory neurons may downregulate their own activity.79,80”
From Glutamate in Schizophrenia: A Focused Review and Meta-Analysis of 1H-MRS Studies (2013) · cites this paper as [80]
In the citing paper
“The prefrontal cortex (PFC) and hippocampus stand out as major regions affected in schizophrenia”
From Adolescent Onset of Cortical Disinhibition in Schizophrenia: Insights From Animal Models (2011) · cites this paper as [2]
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Metadata
- Authors
- Lewis, D. A., & Moghaddam, B.
- Affiliations
- University of Pittsburgh (US)
- Venue
- Archives of Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2006-10-01
- Volume
- 63
- Issue
- 10
- Pages
- 1372
- ISSN
- 0003-9942 (ISSN-L)
- OpenAlex
- W2037549116
- Cited by
- 404
- References
- 41
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 11 · 2023: 6 · 2022: 9 · 2021: 11 · 2020: 11 · 2019: 12 · 2018: 16 · 2017: 13 · 2016: 17 · 2015: 22 · 2014: 28 · 2013: 25 · 2012: 39
- FWCI
- 20.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Archives of Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Pittsburgh
- National Alliance for Research on Schizophrenia and Depression
- National Institutes of Health (5r01mh048404-30, MH043784, MH045156)
- National Institute of Mental Health (MH-045156, R01-MH048404, MH051234, R37MH048404, R01MH051234, P50MH045156, MH065026, R21MH065026, MH043784, MH048404)
- 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, cognitive impairment, working memory, dorsolateral prefrontal cortex, GABAergic inhibition, glutamatergic excitation, parvalbumin, NMDA receptor, neuronal synchronization, therapeutic target
- MeSH terms
- Animals, Cognition Disorders, gamma-Aminobutyric Acid, Humans, Neural Inhibition, Synaptic Transmission, Schizophrenia, Receptors, N-Methyl-D-Aspartate, Prefrontal Cortex, Pyramidal Cells, Glutamic Acid
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 ›
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