A necessity for MAP kinase activation in mammalian spatial learning - PubMed (original) (raw)

A necessity for MAP kinase activation in mammalian spatial learning

J C Selcher et al. Learn Mem. 1999 Sep-Oct.

Abstract

Although the biochemical mechanisms underlying learning and memory have not yet been fully elucidated, mounting evidence suggests that activation of protein kinases and phosphorylation of their downstream effectors plays a major role. Recent findings in our laboratory have shown a requirement for the mitogen-activated protein kinase (MAPK) cascade in hippocampal synaptic plasticity. Therefore, we used an inhibitor of MAPK activation, SL327, to test the role of the MAPK cascade in hippocampus-dependent learning in mice. SL327, which crosses the blood-brain barrier, was administered intraperitoneally at several concentrations to animals prior to cue and contextual fear conditioning. Administration of SL327 completely blocked contextual fear conditioning and significantly attenuated cue learning when measured 24 hr after training. To determine whether MAPK activation is required for spatial learning, we administered SL327 to mice prior to training in the Morris water maze. Animals treated with SL327 exhibited significant attenuation of water maze learning; they took significantly longer to find a hidden platform compared with vehicle-treated controls and also failed to use a selective search strategy during subsequent probe trials in which the platform was removed. These impairments cannot be attributed to nonspecific effects of the drug during the training phase; no deficit was seen in the visible platform task, and injection of SL327 following training produced no effect on the performance of these mice in the hidden platform task. These findings indicate that the MAPK cascade is required for spatial and contextual learning in mice.

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Figures

Figure 1

SL327 inhibits MAPK activation in the hippocampus. (A) Both p42 and p44 phospho-MAPK levels were significantly inhibited 60 min after injection with 30 or 50 mg/kg SL327. There was no concurrent decrease in total MAPK levels for either isoform with any concentration of SL327 tested. (black bar) DMSO; (white bar) 10 mg/kg; (gray bar) 30 mg/kg; (hatched bar) 50 mg/kg. (B) The time course of the effect of SL327 is shown. The level of phosphorylated MAPK decreased 30 min after SL327 injection and remained below baseline levels for at least 3 hr. [(○)] p42 (phospho MAPK; [(●)] p42 (total MAPK). There was no change in the level of total MAPK during the 3 hr following drug injection. For all figures, data represents mean ±

s.e.m.

. (**) P <0.01; (*) P <0.05.

Figure 1

s.e.m.

. (**) P <0.01; (*) P <0.05.

Figure 2

Administration of SL327 during training blocks contextual fear conditioning and significantly attenuates cue learning in a dose-dependent manner. (A) Freezing responses during the training phase are shown. A tone (solid bar) was paired with a foot shock (arrow) between minutes 3 and 4. (●) DMSO; (□) 10 mg/kg SL327; (▵) 30 mg/kg SL327. Baseline behavior (before presentation of the tone) and shock response (after the foot shock) were similar for all groups. (B) Mice given SL327 (10 mg/kg, n = 5 or 30 mg/kg, n = 7) showed significant reductions in freezing to the context 24 hr after receiving one pairing of tone and shock as compared with animals injected with vehicle (n = 6), left. Administration of 10 or 30 mg/kg SL327 was also sufficient to significantly attenuate freezing to the cue (CS–PreCS), right. (C) When animals were trained with three pairings of tone and foot shock, 10 mg/kg and 30 mg/kg SL327 (10 mg/kg, n = 6 or 30 mg/kg, n = 7) blocked freezing to the context compared with vehicle (n = 10), left. The additional pairings of tone and shock eliminated any effect of SL327 on freezing in response to the cue, right. There was no difference between the PreCS values for any of the groups with either the 1× or 3× paradigms. (**) P <0.01; (*) P <0.05.

Figure 3

Injection of SL327 produces significantly longer escape latencies in the hidden platform version, but not the visible platform version of the Morris water maze task. (A) Average escape latency during training on the hidden platform task. Performance for mice injected with vehicle (n = 13) improved over the course of the training. SL327-treated mice (n = 11) took significantly longer to locate the escape platform. The dark vertical line between blocks 10 and 11 represents the drug switch on day 6. On that day, SL327-trained mice (▵) received DMSO (n = 9), whereas DMSO-trained animals (●) received SL327 (n = 11). (B) Average escape latency during training on the visible platform task. Performance for both mice treated with SL327 (n = 5) and those treated with vehicle (n = 5) improved during training and there was no significant difference between the two groups. Although it is not necessary for the performance of the task, rats trained on the fixed visible platform task develop a cognitive map of the platform's location in relation to the visual cues outside the pool (R. Paylor, unpubl.). When the platform is removed and a probe test is given, these animals display a selective search strategy. Because we trained our mice using a fixed visible platform paradigm, we investigated whether these animals also passively acquired this spatial information. Neither SL327-treated nor vehicle-treated animals searched for the platform selectively during probe tests given after training on days 2 and 3 (data not shown).(○) Control; (▴) SL327.

Figure 4

Administration of SL327 significantly impaired spatial learning performance in the Morris water maze task. (A) During the probe trials on days 4 and 5, mice treated with vehicle (n = 13) spent significantly more time searching in the trained quadrant and crossed the platform area in the trained quadrant more frequently than in any of the alternate quadrants. However, mice injected with 30 mg/kg SL327 (n = 11) did not exhibit a selective search strategy. There was no significant difference between the time spent in the trained quadrant and platform crossings as compared with the other quadrants. (B) The drug treatment was switched on day 6; animals who had received SL327 during the first 5 days now received vehicle and vice versa. The vehicle-trained mice (n = 11) still exhibited a selective search strategy after injection with SL327 on day 6. SL327-trained mice (n = 9) who were administered vehicle on day 6, did not display a selective search strategy. (***) Significantly larger (P <0.01) than all three of the other quadrants.

Figure 5

Mice treated with SL327 failed to exhibit a spatial strategy when searching for the platform during probe trials. A selective search strategy is one in which the subject spends significantly more time searching in the trained quadrant than in the other three quadrants. The subject must also cross the area where the platform had been during the training sessions significantly more often than they cross the corresponding areas in the other quadrants. (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 nine 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 platform area only once and spent 32% of the time in this quadrant (vs. 34% in the opposite quadrant).

Figure 5

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A necessity for MAP kinase activation in mammalian spatial learning - PubMed (original) (raw)