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Synaptic plasticity impairment and hypofunction of NMDA receptors induced by glutathione deficit: Relevance to schizophrenia
Abstract
Increasing evidence suggests that the metabolism of glutathione, an endogenous redox regulator, is abnormal in schizophrenia. Patients show a deficit in glutathione levels in the cerebrospinal fluid and prefrontal cortex and a reduction in gene expression of the glutathione synthesizing enzymes. We investigated whether such glutathione deficit altered synaptic transmission and plasticity in slices of rat hippocampus, with particular emphasis on NMDA receptor function. An approximately 40% decrease in brain glutathione levels was induced by s.c. administration of L-buthionine-(S,R)-sulfoximine, an inhibitor of glutathione synthesis. Such glutathione deficit did not affect the basal synaptic transmission, but produced several NMDA receptor-dependent and -independent effects. Glutathione deficit caused an increase in excitability of CA1 pyramidal cells. The paired-pulse facilitation was diminished in glutathione-depleted slices, in a manner that was independent of NMDA receptor activity. This suggests that lowering glutathione levels altered presynaptic mechanisms involved in neurotransmitter release. NMDA receptor-dependent long-term potentiation induced by high-frequency stimulation was impaired in glutathione-depleted slices. Pharmacologically isolated NMDA receptor-mediated field excitatory postsynaptic potentials were significantly smaller in L-buthionine-(S,R)-sulfoximine-treated than in control slices. Hypofunction of NMDA receptors under glutathione deficit was explained at least in part by an excessive oxidation of the extracellular redox-sensitive sites of the NMDA receptors. These results indicate that a glutathione deficit, like that observed in schizophrenics, alters short- and long-term synaptic plasticity and affects NMDA receptor function. Thus, glutathione deficit could be one causal factor for the hypofunction of NMDA receptors in schizophrenia.
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“Ageassociated shifts in intracellular redox state to a pro-oxidizing environment have been linked to reduced NMDAR activity via the redox regulation of calcium/ calmodulin-dependent protein kinase type II (CaMKII), and can be rescued by intracellular GSH 72 .”
From Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis (2016) · cites this paper as [72]
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Metadata
- Authors
- Steullet, P., Neijt, H. C., Cuénod, M., & Do, K. Q.
- Affiliations
- Centre Hospitalier Universitaire Vaudois (CH)
- Novartis (Switzerland) (CH)
- University of Lausanne (CH)
- Venue
- Neuroscience
- Publisher
- Elsevier BV
- Published
- 2006-01
- Volume
- 137
- Issue
- 3
- Pages
- 807-819
- ISSN
- 0306-4522 (ISSN-L)
- OpenAlex
- W2004830149
- Cited by
- 173
- References
- 87
- Citations by year
- 2025: 4 · 2024: 3 · 2023: 4 · 2022: 5 · 2021: 13 · 2020: 6 · 2019: 6 · 2018: 10 · 2017: 12 · 2016: 11 · 2015: 12 · 2014: 11 · 2013: 9 · 2012: 16
- FWCI
- 2.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- NMDA receptor hypofunction, synaptic plasticity, schizophrenia, L-buthionine sulfoximine, glutathione synthesis inhibition, paired-pulse facilitation, long-term potentiation, presynaptic neurotransmitter release, hippocampus, glutathione metabolism
- MeSH terms
- Animals, Antimetabolites, Electric Stimulation, Electrophysiology, Glutamate-Cysteine Ligase, Glutathione, Membrane Potentials, Synaptic Transmission, Neuronal Plasticity, Schizophrenia, Synapses, Receptors, N-Methyl-D-Aspartate, Rats, Wistar, Long-Term Potentiation, Buthionine Sulfoximine, Excitatory Postsynaptic Potentials, Rats, In Vitro Techniques
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