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Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5
Abstract
Recent work has shown that the hippocampus contains a class of receptors for the excitatory amino acid glutamate that are activated by N-methyl-D-aspartate (NMDA) and that exhibit a peculiar dependency on membrane voltage in becoming active only on depolarization. Blockade of these sites with the drug aminophosphonovaleric acid (AP5) does not detectably affect synaptic transmission in the hippocampus, but prevents the induction of hippocampal long-term potentiation (LTP) following brief high-frequency stimulation. We now report that chronic intraventricular infusion of D,L-AP5 causes a selective impairment of place learning, which is highly sensitive to hippocampal damage, without affecting visual discrimination learning, which is not. The L-isomer of AP5 did not produce behavioural effects. AP5 treatment also suppressed LTP in vivo. These results suggest that NMDA receptors are involved in spatial learning, and add support to the hypothesis that LTP is involved in some, but not all, forms of learning.
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“Morris et al. (1986) were the first to show that rats that received infusion of AP5 into the hippocampus were deficient in performing a spatial memory task in which the animals are required to form multiple spatial relations between a hidden platform in a circular pool (known as a water maze) and visible objects in the surrounding environment and swim to the platform toescape from the water.”
From The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory. (1996) · cites this paper as Morris et al. (1986)
In the citing paper
“Additionally, NMDAR-dependent LTP has been most tightly associated with intact animal behavioral memory (19, 43–46).”
From Synaptic memory and CaMKII (2023) · cites this paper as [45]
In the citing paper
“However, although there is considerable evidence linking LTP to behavior memory (45, 441–443), more evidence is needed to solidify this link.”
From Synaptic memory and CaMKII (2023) · cites this paper as [45]
In the citing paper
“Genetically-modified mouse models of NMDA hypofunctionincluding the Grin1 hypomorphic mouse 25 and the Srr knockout mouse 26 -have also revealed schizophrenia-relevant phenotypes and neurochemical deficits.”
From Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis (2016) · cites this paper as [26]
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Metadata
- Authors
- Morris, R. G. M., Anderson, E., Lynch, G. S., & Baudry, M.
- Affiliations
- University of St Andrews (GB)
- University of California, Irvine (US)
- Venue
- Nature
- Published
- 1986-02
- Volume
- 319
- Issue
- 6056
- Pages
- 774-776
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2025801062
- Cited by
- 3,640
- References
- 19
- Citations by year
- 2026: 25 · 2025: 30 · 2024: 44 · 2023: 31 · 2022: 42 · 2021: 63 · 2020: 52 · 2019: 65 · 2018: 83 · 2017: 85 · 2016: 82 · 2015: 89 · 2014: 103 · 2013: 98 · 2012: 101
- FWCI
- 31.77
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- NMDA receptor, AP5, long-term potentiation, hippocampus, place learning, spatial learning, visual discrimination learning, glutamate receptors, intraventricular infusion, synaptic plasticity
- MeSH terms
- Animals, Electric Stimulation, Hippocampus, Isomerism, Learning, Valine, Visual Perception, 2-Amino-5-phosphonovalerate, Receptors, N-Methyl-D-Aspartate, Receptors, Neurotransmitter, Rats
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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.
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