The NMDA receptor antagonist D-2-amino-5-phosphonopentanoate (D-AP5) impairs spatial learning and LTP in vivo at intracerebral concentrations comparable to those that block LTP in vitro

Abstract

This series of experiments investigated whether the NMDA receptor antagonist D-2-amino-5-phosphonopentanoate (D-AP5) could induce impairments of spatial learning across a dose range comparable to its impairment of hippocampal long-term potentiation (LTP) in vivo. Estimations of the extracellular concentration of D-AP5 in hippocampus using microdialysis were also made to compare whether these impairments occur at concentrations similar to those required to impair LTP in the in vitro hippocampal slice. Rats were chronically infused with D-AP5 into the lateral ventricle at a range of concentrations (0–50 mM) via osmotic minipumps. They were first trained to find and escape onto a hidden platform in an open-field water maze task. After the behavioral learning, they were anesthetized with urethane and an attempt was made to evoke and monitor hippocampal LTP. Extracellular samples of D-AP5 in hippocampus were then taken using microdialysis, and finally, the animals were killed and tissue samples dissected. The microdialysis and tissue samples were analyzed for D-AP5 content using HPLC with fluorescence detection. The results established, first, that D-AP5 impairs spatial learning in a linear dose-dependent manner, highly correlated with its corresponding impairment of hippocampal LTP in vivo. No concentration of D-AP5 was observed to block LTP without affecting learning. Second, the microdialysis estimates indicated that, subject to certain assumptions, D-AP5 causes these impairments at extracellular concentrations comparable to those that impair LTP in vitro. Third, comparison of the whole tissue and microdialysis samples revealed a concentration ratio of approximately 30:1, indicating that 97% of the intracerebral D-AP5 is inaccessible to the dialysis probes. Infusion of 20 mM EGTA was found to cause a sevenfold increase in D-AP5 in the dialysis perfusates, suggesting that at least part of the inaccessible D-AP5 is trapped by a calcium-dependent mechanism. Two further behavioral control studies indicated that the D-AP5-induced impairment of spatial learning is unlikely to be secondary to a drug- induced motor disturbance, and that the performance of the D-AP5 group whose concentration was just sufficient to block hippocampal LTP completely was statistically indistinguishable from that of a group of rats with bilateral hippocampal lesions induced by ibotenic acid. Taken together, these findings offer support for the hypothesis that activation of NMDA receptors is necessary for certain kinds of learning.

Long‐term potentiation and the mechanisms of memory

“…The c-fos induction effect was also seen after one trial of inhibitory avoidance in the chick brain [Anokhin and Rose, 19911 or after nine daily sessions of two-way avoidance in several regions of the rat cortex [Nikolaev et al, 19921. This behavior is at least partly dependent on hippocampal function [Calderazzo Filho et al, 1977;Gray and McNaughton, 19831. The finding of Nikolaev et al [1992] is in contrast with a previous report [Wisden et al, 19901, where no change of the expression of c-fos in the hippocampus following training in the water maze was observed, a task that is very much dependent on the hippocampus [Davis et al, 1992;Morris, 1990;Morris et al, 19861. It is not known to what extent LTP maintenance depends on pre-or on postsynaptic mechanisms. Perhaps, as was discussed above in relation to induction mechanisms, the most parsimonious guess is that LTP maintenance is regulated by both pre-and postsynaptic mechanisms [Colley and Routtenberg, 1993;Routtenberg, 19901.…”

Learning and hippocampal synaptic plasticity in streptozotocin-diabetic rats: interaction of diabetes and ageing

“…These alterations in synaptic plasticity were associated with learning impairments in a Morris-water maze [10,12]. An association between alterations in hippocampal LTP and learning impairments has also been reported in ageing animals [13] and in response to various pharmacological and molecular manipulations [14,15], supporting the functional relevance of the link between these two variables.…”

The increase in medial prefrontal glutamate/glutamine concentration during memory encoding is associated with better memory performance and stronger functional connectivity in the human medial prefrontal–thalamus–hippocampus network

“…Manipulating glutamatergic receptors appear to affect LTP and memory. For instance, blocking glutamatergic transmission via an NMDA receptor antagonist causes LTP reduction and impaired learning (Davis et al,1992; Stäubli et al,1994). Therefore, the assumption of increased glutamatergic transmission would be in line with our finding regarding memory performance.…”