Extracellular signal-regulated kinase activity in the entorhinal cortex is necessary for long-term spatial memory

Abstract

Lesion studies have provided evidence that the entorhinal cortex (EC) participates in spatial memory. However, the molecular cascades that underlie memory-associated changes in the EC and its specific role in spatial memory, however, have not been clearly delineated. Recently, it has been shown that activation of extracellular signal-regulated kinase (Erk, a mitogen-activated protein kinase family member) in the dorsal hippocampus is necessary for spatial memory. To examine whether similar mechanisms are used for spatial memory storage in the EC, Erk activity was inhibited after training in the Morris water maze. Bilateral infusion of the mitogen-activated protein kinase kinase inhibitor PD098059 into the EC immediately after training resulted in a memory deficit observed during a retention test performed 48 h later. This deficit was abolished with pretraining in a different water maze in which animals were able to learn the general task requirements and the appropriate search strategies. The absence of a deficit indicates that Erk activity in the EC may be involved in storing the task requirements or the search strategies. The findings presented in this article are consistent with the idea that the EC is involved in spatial memory and indicate that Erk activity is necessary for memory consolidation in this structure.

Figure 1

PD098059 infusion into the entorhinal cortex (EC) prevents extracellular signal-regulated kinase (Erk) activation. (A) Representative photomicrographs showing decreased phospho-Erk immunoreactivity in the entorhinal area after 0.2 μg PD098059 infusion into one side compared with the vehicle-infused contralateral side (10-min time point). (B) In adjacent slices, 0.2 μg PD098059 does not decrease CREB immunoreactivity. (C) In the dorsal hippocampus in the same animal, 0.2 μg PD098059 infused into the EC does not decrease phospho-Erk.

Figure 2

Infusion sites in the EC. Infusion sites in the entorhinal area for all behavioral experiments as shown on coronal atlas plates taken from Paxinos and Watson (1997). Infusion sites are indicated by circles. Only animals that had infusion sites within the EC and that were 0.8 mm rostral-caudal of the target site were kept for further analysis.

Figure 3

Infusion of PD098059 into the EC after training in the Morris water maze blocks long-term memory. Arrow indicates time of infusion (0.2 μg/side of PD098059 [n = 9] or vehicle [n = 7]). (A) Latency to the platform location during training and the probe trial. (B) Representative traces of the probe trials for vehicle- and drug-infused animals. (C) Dwell time in the outer 50% of the tank before the first successful attempt during the probe trial. (D) Heading error as the angle away from the target (deg) leaving the entry quadrant during the probe trial. (E) Latency to the platform during retraining. Data are presented as the mean ± standard error of mean (SEM), * p < .05.

Figure 4

Pretraining in a separate water maze facilitates training. (A) Latency to the platform during the first pretraining trial (Blue) versus the first training trial (Yellow). (B) Average number of trials to criterion for non-pretrained (NPT) animals from Experiment 1 versus the pretrained (PT) animals from Experiment 2. (C) Training curves broken down into individual trials. Latency to platform during the first seven training trials for NPT animals from Experiment 1 versus the PT animals from Experiment 2 (two-way repeated measures analysis of variance [ANOVA] on Ranks NPT versus PT p < .05). Data are presented as the mean ± SEM, * p < .05.

Figure 5

Pretraining prevents the memory deficit induced by PD098059 infusion into the EC. Arrow indicates time of infusion (0.2 μg/side of PD098059 [n = 10] or vehicle [n = 13]). (A) Latency to platform location during pretraining, the first probe trial, training, and the second probe trial. (B) Representative traces of the probe trials for animals from the vehicle (n = 13) and drug (n = 10) groups. (C) Dwell time in the outer 50% of the tank before the first successful attempt during the probe trial. (D) Heading error as the angle away from the target (deg) leaving the entry quadrant during the probe trial. (E) Latency to the platform location during retraining. Data are presented as the mean ± SEM.