ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2012
Synaptic NMDA receptors mediate hypoxic excitotoxic death.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 79 papers.
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Who cites it
79 citing papers in PubMed, 138 citations in OpenAlex.
- Memantine: updates from the past decade and implications for future novel therapeutic applications.Journal of neural transmission (Vienna, Austria : 1996) · 2026Review
- Aberrant coupling of glutamate and tyrosine kinase receptors enables neuronal control of brain-tumor growth.Neuron · 2025Article
- Redox modulation of the complement cascade contributes to synapse loss in Alzheimer's disease.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025Review
- Neural Processing without OPhysiology (Bethesda, Md.) · 2024Review
- NMDA Receptors: Distribution, Role, and Insights into Neuropsychiatric Disorders.Pharmaceuticals (Basel, Switzerland) · 2024Review
- The GluN2B-Containing NMDA Receptor Alleviates Neuronal Apoptosis in Neonatal Hypoxic-Ischemic Encephalopathy by Activating PI3K-Akt-CREB Signaling Pathwa.Physiological research · 2023Article
- Tonic Activation of NR2D-Containing NMDARs Exacerbates Dopaminergic Neuronal Loss in MPTP-Injected Parkinsonian Mice.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2023Article
- A single dose of ketamine enhances early life stress-induced aggression with no effect on fear memory, anxiety-like behavior, or depression-like behavior in mice.Behavioral neuroscience · 2023Article
- Pharmacological Characterization of [Molecular imaging and biology · 2023Article
- Extrasynaptic NMDA receptors in acute and chronic excitotoxicity: implications for preventive treatments of ischemic stroke and late-onset Alzheimer's disease.Molecular neurodegeneration · 2023Review
- Phase 1 Clinical Results for NP10679, a pH-sensitive GluN2B-selective N-methyl-d-aspartate Receptor Inhibitor.Clinical pharmacology in drug development · 2023Article
- The combination of Astragalus membranaceus and ligustrazine mitigates cerebral ischemia-reperfusion injury via regulating NR2B-ERK/CREB signaling.Brain and behavior · 2023Article
- The use of ketamine as a neuroprotective agent following cardiac arrest: A scoping review of current literature.CNS neuroscience & therapeutics · 2023Article
- Engineered Neutral Phosphorous Dendrimers Protect Mouse Cortical Neurons and Brain Organoids from Excitotoxic Death.International journal of molecular sciences · 2022Article
- Promises and Pitfalls of NMDA Receptor Antagonists in Treating Violent Aggression.Frontiers in behavioral neuroscience · 2022Article
- Extracellular Calcium Influx Pathways in Astrocyte Calcium Microdomain Physiology.Biomolecules · 2021Review
- Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels.Pharmacological reviews · 2021Review
- Building a Bridge Between NMDAR-Mediated Excitotoxicity and Mitochondrial Dysfunction in Chronic and Acute Diseases.Cellular and molecular neurobiology · 2021Review
- The diverse and complex modes of action of anti-NMDA receptor autoantibodies.Neuropharmacology · 2021Review
- Amyloid Beta-Mediated Changes in Synaptic Function and Spine Number of Neocortical Neurons Depend on NMDA Receptors.International journal of molecular sciences · 2021Article
19 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Excessive NMDA receptor activation and excitotoxicity underlies pathology in many neuropsychiatric and neurological disorders, including hypoxia/ischemia. Thus, the development of effective therapeutics for these disorders demands a complete understanding of NMDA receptor (NMDAR) activation during excitotoxic insults. The extrasynaptic NMDAR hypothesis posits that synaptic NMDARs are neurotrophic/neuroprotective and extrasynaptic NMDARs are neurotoxic. The extrasynaptic hypothesis is built in part on observed selectivity for extrasynaptic receptors of a neuroprotective use-dependent NMDAR channel blocker, memantine. In rat hippocampal neurons, we found that a neuroprotective concentration of memantine shows little selectivity for extrasynaptic NMDARs when all receptors are tonically activated by exogenous glutamate. This led us to test the extrasynaptic NMDAR hypothesis using metabolic challenge, where the source of excitotoxic glutamate buildup may be largely synaptic. Three independent approaches suggest strongly that synaptic receptors participate prominently in hypoxic excitotoxicity. First, block of glutamate transporters with a nonsubstrate antagonist exacerbated rather than prevented damage, consistent with a primarily synaptic source of glutamate. Second, selective, preblock of synaptic NMDARs with a slowly reversible, use-dependent antagonist protected nearly fully against prolonged hypoxic insult. Third, glutamate pyruvate transaminase, which degrades ambient but not synaptic glutamate, did not protect against hypoxia but protected against exogenous glutamate damage. Together, these results suggest that synaptic NMDARs can mediate excitotoxicity, particularly when the glutamate source is synaptic and when synaptic receptor contributions are rigorously defined. Moreover, the results suggest that in some situations therapeutically targeting extrasynaptic receptors may be inappropriate.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.