N-methyl-d-aspartate receptors, learning and memory: chronic intraventricular infusion of the NMDA receptor antagonist d-AP5 interacts directly with the neural mechanisms of spatial learning

R. G. M. Morris (Lead / Corresponding author), R. J. Steele, J. E. Bell, S. J. Martin

    Research output: Contribution to journalArticle

    35 Citations (Scopus)

    Abstract

    Three experiments were conducted to contrast the hypothesis that hippocampal N-methyl-d-aspartate (NMDA) receptors participate directly in the mechanisms of hippocampus-dependent learning with an alternative view that apparent impairments of learning induced by NMDA receptor antagonists arise because of drug-induced neuropathological and/or sensorimotor disturbances. In Experiment 1, rats given a chronic i.c.v. infusion of d-AP5 (30mm) at 0.5L/h were selectively impaired, relative to aCSF-infused animals, in place but not cued navigation learning when they were trained during the 14-day drug infusion period, but were unimpaired on both tasks if trained 11days after the minipumps were exhausted. d-AP5 caused sensorimotor disturbances in the spatial task, but these gradually worsened as the animals failed to learn. Histological assessment of potential neuropathological changes revealed no abnormalities in d-AP5-treated rats whether killed during or after chronic drug infusion. In Experiment 2, a deficit in spatial learning was also apparent in d-AP5-treated rats trained on a spatial reference memory task involving two identical but visible platforms, a task chosen and shown to minimise sensorimotor disturbances. HPLC was used to identify the presence of d-AP5 in selected brain areas. In Experiment 3, rats treated with d-AP5 showed a delay-dependent deficit in spatial memory in the delayed matching-to-place protocol for the water maze. These data are discussed with respect to the learning mechanism and sensorimotor accounts of the impact of NMDA receptor antagonists on brain function. We argue that NMDA receptor mechanisms participate directly in spatial learning.

    Original languageEnglish
    Pages (from-to)700-717
    Number of pages18
    JournalEuropean Journal of Neuroscience
    Volume37
    Issue number5
    DOIs
    Publication statusPublished - Mar 2013

    Keywords

    • cingulate cortex
    • delay-dependent deficit
    • hippocampus
    • MK-801
    • sensorimotor disturbances
    • water maze
    • LONG-TERM POTENTIATION
    • DEPENDENT SYNAPTIC PLASTICITY
    • WORKING-MEMORY
    • INTRAHIPPOCAMPAL INFUSION
    • SELECTIVE IMPAIRMENT
    • INFORMATION-STORAGE
    • MAZE PERFORMANCE
    • HIPPOCAMPAL NMDA
    • AMPA RECEPTORS
    • WATER MAZE

    Cite this

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    title = "N-methyl-d-aspartate receptors, learning and memory: chronic intraventricular infusion of the NMDA receptor antagonist d-AP5 interacts directly with the neural mechanisms of spatial learning",
    abstract = "Three experiments were conducted to contrast the hypothesis that hippocampal N-methyl-d-aspartate (NMDA) receptors participate directly in the mechanisms of hippocampus-dependent learning with an alternative view that apparent impairments of learning induced by NMDA receptor antagonists arise because of drug-induced neuropathological and/or sensorimotor disturbances. In Experiment 1, rats given a chronic i.c.v. infusion of d-AP5 (30mm) at 0.5L/h were selectively impaired, relative to aCSF-infused animals, in place but not cued navigation learning when they were trained during the 14-day drug infusion period, but were unimpaired on both tasks if trained 11days after the minipumps were exhausted. d-AP5 caused sensorimotor disturbances in the spatial task, but these gradually worsened as the animals failed to learn. Histological assessment of potential neuropathological changes revealed no abnormalities in d-AP5-treated rats whether killed during or after chronic drug infusion. In Experiment 2, a deficit in spatial learning was also apparent in d-AP5-treated rats trained on a spatial reference memory task involving two identical but visible platforms, a task chosen and shown to minimise sensorimotor disturbances. HPLC was used to identify the presence of d-AP5 in selected brain areas. In Experiment 3, rats treated with d-AP5 showed a delay-dependent deficit in spatial memory in the delayed matching-to-place protocol for the water maze. These data are discussed with respect to the learning mechanism and sensorimotor accounts of the impact of NMDA receptor antagonists on brain function. We argue that NMDA receptor mechanisms participate directly in spatial learning.",
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    N-methyl-d-aspartate receptors, learning and memory : chronic intraventricular infusion of the NMDA receptor antagonist d-AP5 interacts directly with the neural mechanisms of spatial learning. / Morris, R. G. M. (Lead / Corresponding author); Steele, R. J.; Bell, J. E.; Martin, S. J.

    In: European Journal of Neuroscience, Vol. 37, No. 5, 03.2013, p. 700-717.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - N-methyl-d-aspartate receptors, learning and memory

    T2 - chronic intraventricular infusion of the NMDA receptor antagonist d-AP5 interacts directly with the neural mechanisms of spatial learning

    AU - Morris, R. G. M.

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    AU - Martin, S. J.

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    AB - Three experiments were conducted to contrast the hypothesis that hippocampal N-methyl-d-aspartate (NMDA) receptors participate directly in the mechanisms of hippocampus-dependent learning with an alternative view that apparent impairments of learning induced by NMDA receptor antagonists arise because of drug-induced neuropathological and/or sensorimotor disturbances. In Experiment 1, rats given a chronic i.c.v. infusion of d-AP5 (30mm) at 0.5L/h were selectively impaired, relative to aCSF-infused animals, in place but not cued navigation learning when they were trained during the 14-day drug infusion period, but were unimpaired on both tasks if trained 11days after the minipumps were exhausted. d-AP5 caused sensorimotor disturbances in the spatial task, but these gradually worsened as the animals failed to learn. Histological assessment of potential neuropathological changes revealed no abnormalities in d-AP5-treated rats whether killed during or after chronic drug infusion. In Experiment 2, a deficit in spatial learning was also apparent in d-AP5-treated rats trained on a spatial reference memory task involving two identical but visible platforms, a task chosen and shown to minimise sensorimotor disturbances. HPLC was used to identify the presence of d-AP5 in selected brain areas. In Experiment 3, rats treated with d-AP5 showed a delay-dependent deficit in spatial memory in the delayed matching-to-place protocol for the water maze. These data are discussed with respect to the learning mechanism and sensorimotor accounts of the impact of NMDA receptor antagonists on brain function. We argue that NMDA receptor mechanisms participate directly in spatial learning.

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    KW - DEPENDENT SYNAPTIC PLASTICITY

    KW - WORKING-MEMORY

    KW - INTRAHIPPOCAMPAL INFUSION

    KW - SELECTIVE IMPAIRMENT

    KW - INFORMATION-STORAGE

    KW - MAZE PERFORMANCE

    KW - HIPPOCAMPAL NMDA

    KW - AMPA RECEPTORS

    KW - WATER MAZE

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    JO - European Journal of Neuroscience

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