NMDA receptor plasticity in the perirhinal and prefrontal cortices is crucial for the acquisition of long-term object-in-place associative memory

Abstract

A key process for recognition memory is the formation of associations between an object and the place in which it was encountered, a process that has been shown to require the perirhinal (PRH) and medial prefrontal (mPFC) cortices. Here we demonstrate, for the first time, the importance of glutamatergic neurotransmission, within the PRH and mPFC, for object-in-place associative recognition memory. Unilateral blockade of AMPA receptors (by CNQX) in the PRH and mPFC in opposite hemispheres impaired an object-in-place task in rats, confirming that these cortical regions operate within a neural network for object-in-place recognition memory. Intra-mPFC infusions of AP5 (NMDA receptor antagonist) impaired short-term memory and the acquisition of long-term memory, but had no effect on retrieval. AP5 infusions into the PRH disrupted acquisition of long-term memory, but not short-term memory or retrieval. Significantly, crossed AP5 infusions into both the PRH and mPFC disrupted acquisition of long-term memory but were without effect on short-term memory. Finally a unilateral infusion of the selective kainate (GLU(K5)) receptor antagonist UBP302 [(S)-1-(2-amino-2-carboxyethyl)-3-(2-carboxybenzyl)pyrimidine-2,4-dione] into the PRH combined with a unilateral infusion of AP5 into the contralateral mPFC significantly impaired short-term object-in-place associative memory. These data show that the PRH and mPFC make distinct contributions to object-in-place associative memory and that the encoding of long-term but not short-term memory requires concurrent NMDA receptor activation in both cortical regions. In contrast, short-term object-in-place memory appears to be dependent on kainate receptor activation in the PRH and NMDA receptor activation in the mPFC.

Figure 1.

Diagrammatic representations of the individual infusion sites in each animal. a, Bilateral mPFC group. b, Bilateral PRH group. c, PRH+mPFC group. All of the infusion sites were within the PRH or mPFC.

Figure 2.

Diagram of the two object-recognition memory tasks. a, Object-in-place task. b, Novel object preference task.

Figure 3.

Object-in-place task. Infusion of CNQX into the PRH or mPFC significantly impaired discrimination between the objects that had exchanged location at test and those that remained in the same location. Illustrated for each group is the mean + SEM discrimination ratio. ***p < 0.001, difference between groups.

Figure 4.

Object-in-place task. ai, AP5 infusions into the mPFC before the sample phase significantly impaired object-in-place performance after a 5 min or 1 h delay. *p < 0.05, **p < 0.01, difference between groups. aii, AP5 infusions into the PRH before the sample phase impaired object-in-place performance after a 1 h delay, but not a 5 min delay. **p < 0.01, ***p < 0.001, difference between groups. b, AP5 infusions into the PRH or mPFC before the test phase had no effect on object-in-place performance after a 1 h delay. c, Unilateral AP5 infusions into the PRH and mPFC in opposite hemispheres (AP5 contra) impaired object-in-place performance after a 1 h delay, but not a 5 min delay. AP5 infusion into the PRH and mPFC in the same hemisphere (AP5 ipsi) has no effect on performance. ***p < 0.001, difference between groups.

Figure 5.

Novel object preference task. Perirhinal infusion of AP5 before the sample phase significantly impaired familiarity discrimination after a 1 h delay. **p < 0.01, difference between groups. In contrast, perirhinal infusion of AP5 before the test phase (right histogram) had no effect on familiarity discrimination after a 1 h delay.

Figure 6.

The effect of unilateral AP5 infusions into the PRH and mPFC on object-in-place performance. a, AP5 infusion into the PRH has no effect on object processing after a short retention delay; thus, the disruption only occurs unilaterally within the neural network, and behavioral performance remains intact. b, AP5 infusion into the PRH disrupts object processing after a long delay. As the network is disrupted bilaterally, performance in the object-in-place task is impaired.