Upstairs/downstairs revisited: spatial pretraining‐induced rescue of normal spatial learning during selective blockade of hippocampal N‐methyl‐d‐aspartate receptors

Abstract

Spatial pretraining can enable spatial learning in another environment that ordinarily requires hippocampal N-methyl-d-aspartate (NMDA) receptor activity to become independent of that activity. This study explored further the circumstances in which this training-induced 'rescue' of later learning in the presence of the NMDA receptor antagonist 2-amino-5-phosphonovaleric acid (D-AP5) can occur. D-AP5 (0, 10, 20 and 30 mm in artificial cerebrospinal fluid) was infused continuously (0.5 μL/h, from a minipump) and bilaterally into the dorsal hippocampus during spatial-reference-memory training in a watermaze (4 trials/day, 8 days). This was preceded either by handling only or by identical spatial training in another watermaze in a separate laboratory with different extramaze cues. In naïve rats, D-AP5 caused a dose-related impairment in spatial reference memory acquisition that was significant at the lowest 5 nm/h infusion concentration. In pretrained rats, the dose-response function was shifted such that, in watermaze 2, spatial learning was normal at this low concentration, with a deficit at higher infusion concentrations. The induction of long-term potentiation in the dentate gyrus in vivo was blocked at all D-AP5 concentrations. Sensorimotor abnormalities sometimes seen with NMDA receptor antagonists were only apparent at the highest concentration. The implication of this paradoxical dissociation between hippocampal NMDA receptor-dependent plasticity and spatial learning is discussed with reference to two rival hypotheses of the impact of pretraining.

The search for a hippocampal engram

“…Spatial learning in the second task was still sensitive to hippocampal lesion, showing that circuits through the hippocampus were still required even though NMDA-dependent plasticity was dispensable. This result has been revisited recently with quantitative and anatomically specific NMDA receptor blockade and replicated the basic finding at inhibitor levels sufficient to block dentate gyrus LTP measured in vivo [27]. …”

“…Nevertheless, it seems clear that rodents can form spatial memories even in the absence of hippocampal NMDA receptor function. While there are a number of possible interpretations of these results (for example [27]) taken together, it is difficult to argue that NMDA-dependent LTP in the hippocampus meets the criterion of necessity for a cellular mechanism of spatial learning.…”

Hippocampal NMDA receptors are important for behavioural inhibition but not for encoding associative spatial memories

“…in the absence of any drug), and were then tested in the presence of D-AP5 (30 mM) in a completely novel spatial environment (i.e. a completely different laboratory), then the NMDAR antagonist was now found to have little, if any, effect on acquisition of the open-field, spatial reference memory task (the spatial upstairs/downstairs task [15]; see also [16,17]). Therefore, these pharmacological studies also demonstrated that hippocampal NMDARs are not required for (i) spatial navigation per se , (ii) forming a cognitive map of a novel environment, nor (iii) forming a long-term association between a particular spatial location and an outcome (e.g.…”

The synaptic plasticity and memory hypothesis: encoding, storage and persistence

“…The second issue is that drug diffusion through a brain area is often incomplete such that sub-areas of a given circuit which are less affected by the drug may be used for second learning that are not used for the first [66]. If pharmacological studies have the advantage of 'reversibility', they have the major difficulty that it is extremely difficult to maintain drug concentrations at a steady-state over time or to ensure effective distribution of a drug within a brain area or network without affecting another ostensibly independent region [67].…”