ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2014
Chronic GluN2B antagonism disrupts behavior in wild-type mice without protecting against synapse loss or memory impairment in Alzheimer's disease mouse models.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 25 citations in OpenAlex.
- Targeting synapse function and loss for treatment of neurodegenerative diseases.Nature reviews. Drug discovery · 2024Review
- Memantine Disrupts Motor Coordination through Anxiety-like Behavior in CD1 Mice.Brain sciences · 2022Article
- Differential vulnerability of hippocampal CA3-CA1 synapses to Aβ.Acta neuropathologica communications · 2022Article
- GluN2A NMDA Receptor Enhancement Improves Brain Oscillations, Synchrony, and Cognitive Functions in Dravet Syndrome and Alzheimer's Disease Models.Cell reports · 2020Article
- Animal Models of Psychosis in Alzheimer Disease.The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry · 2020Review
- Insoluble Aβ overexpression in anDisease models & mechanisms · 2019Article
- NMDA receptors mediate synaptic depression, but not spine loss in the dentate gyrus of adult amyloid Beta (Aβ) overexpressing mice.Acta neuropathologica communications · 2018Article
- Higher ambient synaptic glutamate at inhibitory versus excitatory neurons differentially impacts NMDA receptor activity.Nature communications · 2018Article
- Chinese Herbal Medicine Xueshuantong Enhances Cerebral Blood Flow and Improves Neural Functions in Alzheimer's Disease Mice.Journal of Alzheimer's disease : JAD · 2018Article
- Early Activation of Experience-Independent Dendritic Spine Turnover in a Mouse Model of Alzheimer's Disease.Cerebral cortex (New York, N.Y. : 1991) · 2017Article
- Mice deficient in NRROS show abnormal microglial development and neurological disorders.Nature immunology · 2017Article
- Cognitive Deficits, Changes in Synaptic Function, and Brain Pathology in a Mouse Model of Normal Aging(1,2,3).eNeuro · 2015Article
- Altered GluN2B NMDA receptor function and synaptic plasticity during early pathology in the PS2APP mouse model of Alzheimer's disease.Neurobiology of disease · 2015Article
- Long-term NMDAR antagonism correlates reduced astrocytic glutamate uptake with anxiety-like phenotype.Frontiers in cellular neuroscience · 2015Article
- GluN2B-NMDA receptors in Alzheimer's disease: beyond synapse loss and cell death.Neural regeneration research · 2014Article
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Extensive evidence implicates GluN2B-containing NMDA receptors (GluN2B-NMDARs) in excitotoxic-insult-induced neurodegeneration and amyloid β (Aβ)-induced synaptic dysfunction. Therefore, inhibiting GluN2B-NMDARs would appear to be a potential therapeutic strategy to provide neuroprotection and improve cognitive function in Alzheimer's disease (AD). However, there are no reports of long-term in vivo treatment of AD mouse models with GluN2B antagonists. We used piperidine18 (Pip18), a potent and selective GluN2B-NMDAR antagonist with favorable pharmacokinetic properties, for long-term dosing in AD mouse models. Reduced freezing behavior in Tg2576 mice during fear conditioning was partially reversed after subchronic (17 d) Pip18 treatment. However, analysis of freezing behavior in different contexts indicated that this increased freezing likely involves elevated anxiety or excessive memory generalization in both nontransgenic (NTG) and Tg2576 mice. In PS2APP mice chronically fed with medicated food containing Pip18 for 4 months, spatial learning and memory deficits were not rescued, plaque-associated spine loss was not affected, and synaptic function was not altered. At the same time, altered open field activity consistent with increased anxiety and degraded performance in an active avoidance task were observed in NTG after chronic treatment. These results indicate that long-term treatment with a GluN2B-NMDAR antagonist does not provide a disease-modifying benefit and could cause cognitive liabilities rather than symptomatic benefit in AD mouse models. Therefore, these results challenge the expectation of the therapeutic potential for GluN2B-NMDAR antagonists in AD.
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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.