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 (30 mm) at 0.5 μL/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 11 days 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.

Developmental studies of the hippocampus and hippocampal-dependent behaviors: Insights from interdisciplinary studies and tips for new investigators

“…Activation of NMDA receptors has been shown to be critical for activity-dependent synaptic plasticity in the hippocampus (Collingridge and Singer, 1990; Collingridge, 2003; Morris, 1989; Morris et al, 1990), place cell stability (Kentros et al, 2004), and spatial learning and memory (Butcher et al, 1990; Collingridge, 1987; Morris, 1989; Morris et al, 2013). Modification to NMDA receptor composition during late postnatal development is suspected to play a role in age-related improvements in spatial navigation and spatial memory (Dumas, 2005b).…”

Impairment of the anterior thalamic head direction cell network following administration of the NMDA antagonist MK-801

“…Given the widely held view of the critical role of the hippocampal formation in spatial memory (e.g., Jarrard, 1993; Morris, Garrud, Rawlins, & O'Keefe, 1982; Olton, Walker, & Gage, 1978), and the likelihood that NMDA receptor-mediated plasticity may be a cellular mechanism of memory formation in the hippocampus (e.g., Bliss & Collingridge, 1993), it is perhaps not surprising that administration of NMDA antagonists have been shown to impair behavior in a variety of spatial memory paradigms including the Morris water maze (Ahlander, Misane, Schott, Ogren, 1999; Davis, Butcher, & Morris, 1992; Morris, Anderson, Lynch, and Baudry, 1986; Morris, Steele, Bell, & Martin, 2013; Steele and Morris, 1999), the radial arm maze (Butelman, 1989; Ward, Mason, & Abraham, 1990; Shapiro and O'Connor, 1992), and the active allothetic place avoidance task (Stuchlik, and Vales, 2005). …”

d-Aspartic acid stimulates steroidogenesis through the delay of LH receptor internalization in a mammalian Leydig cell line

“…Secondly, we must consider that d-Asp is the precursor of N-methyl-d-Aspartic acid (NMDA), a neurotransmitter known to have a strong involvement on the neuro-endocrine system through its NMDA-specific receptor (NMDA-R) [22]. Since NMDA-R is known to be expressed in the Leydig cells [23], further examination is required to evaluate whether d-Asp acts through a yet unknown specific receptor or it is secondary to the conversion of d-Asp into NMDA [24][25][26].…”