Spatial Learning Requires ERK

Administration of SL327 to mice during training in the Morris water maze produced significant spatial learning deficits. SL327-treated mice took significantly longer to locate the escape platform during training compared to vehicle-treated controls (Fig. 5). Furthermore, vehicle-treated control mice performed significantly better than drug-treated animals in probe trials conducted following training suggesting that SL327 impairs spatial learning performance (Figs. 6 and 7). These results demonstrate a necessity for ERK activation in spatial learning.

These findings are consistent with those reported by Dash and colleagues29 who described an increase in ERK phosphorylation in pyramidal cells of the CA1/CA2 subfield of the dorsal hippocampus in response to behavioral training in the Morris water maze.17 This group also demonstrated a necessity for ERK activation for spatial learning in rats, although they only saw behavioral impairments on the first retention trial 48 hours after training following PD098059 infusions into the hippocampus. These differences seen in the two studies could be due to different training or testing paradigms, species of test subjects, or differences in the efficacy and time course of MEK inhibition by SL327 versus PD098059. One particularly intriguing possibility to explain the different observations is the locus of the drug effect. While Dash and colleagues29 selectively infused a MEK inhibitor into the hippocampus, our intraperitoneal administration of SL327 inhibits MEK throughout the central nervous system. Thus, the observed differences might simply be accounted for by involvement of ERK activation in extra-hippocampal areas during spatial learning.

When administered post-training, SL327 produced no impairments in water maze performance, demonstrating that inhibition of ERK activation had virtually no effect on the performance of animals that had already learned the water maze task (Figs. 5 and 8). This suggests that ERK activation is required for the formation of memory, but is unnecessary for ongoing maintenance of memory. These results are consistent with the LTP studies involving ERK performed by English et al,38 in which application of PD098059 before tetanization was shown to block the induction of LTP whereas PD098059 application 30 min after tetanization had no effect on the expression of established LTP.

Figure 6. Administration of SL327 significantly impaired spatial learning in the Morris water maze. A) During the probe trials on days 4 and 5, mice treated with vehicle crossed the area where the platform had been in the trained quadrant significantly more frequently than a corresponding area in the alternate quadrants. SL327-treated mice did not exhibit the same selectivity in their search. B) Control mice spent significantly more time searching in the trained quadrant than in any of the alternate quadrants. However, mice injected with 30 mg/kg SL327 did not spend more time searching in the trained quadrant. The dotted line represents chance (25% of the time in each quadrant). ***sig-nificantly larger (p < 0.01) than all three of the other quadrants.

Figure 7. Mice treated with SL327 failed to employ a spatial search strategy during probe trials. A) Representative probe trial of a vehicle-treated mouse. The swim path trace shown here provides an excellent example of a selective search. This particular subject was trained with the platform located in the northeast quadrant. During the probe trial, this mouse spent 56% of the time in the correct quadrant and crosses the exact area where the platform had been 9 times. B) Representative probe trial of an SL327-treated mouse.This trace does not represent a selective search. This mouse was trained with the platform in the northwest quadrant, but during the probe trial, the subject crossed this patform area only once and spent 32% of the time in this quadrant (versus 34% in the opposite quadrant).

Figure 8. SL327 had little effect on mice that had previously learned the Morris water maze task. After administration of SL327 on day 6 (drug switch), the vehicle-trained mice still showed significantly more platform crossings (A) and spent more time searching (B) in the trained quadrant compared to the other three quadrants. SL327-trained mice who were administered vehicle on day 6 did not display a selective search strategy. ***significantly larger (p < 0.05) than all three of the other quadrants. ^significantly larger (p < 0.05) than right and opposite quadrants, but not quite significantly different than the left quadrant (p = 0.06).

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