A specific role for group I mGluRs in hippocampal LTP and hippocampus-dependent spatial learning

Abstract

Metabotropic glutamate receptors (mGluRs) have been implicated in long-term potentiation and in learning and memory formation. In this study, we tested the effects of group I mGluR inhibition on synaptic plasticity and learning of rats at different levels of organization (1) in the hippocampal slice preparation; (2) in freely moving animals implanted with chronic hippocampal electrodes; and (3) in different spatial learning paradigms. To allow a direct comparison of the effects obtained the same doses were used in all paradigms. Bath-application of the selective group I mGluR antagonist (S)4-carboxyphenylglycine (4-CPG) impaired a decremental long-term potentiation (LTP) induced by a weak tetanization paradigm, but failed to affect a robust LTP generated by strong tetanization. In contrast, 4-CPG impaired a robust LTP in freely moving animals if applied 30 min before tetanization. The same dose of 4-CPG only impeded spatial learning mildly in the eight-arm radial maze and had no effect on a simple configuration of the Y-maze spatial alternation task. In the more difficult configuration of this task, however, 4-CPG caused complete amnesia. The lack of state-dependent 4-CPG actions and the absence of any 4-CPG effects in the open-field test classify the obtained retention deficit as a selective impairment of memory storage. Our results indicate a specific role of group I mGluRs in certain types of synaptic plasticity and of spatial learning.

Figure 1

Under in vitro conditions, the mGluR group I antagonist 4-CPG impairs LTP induced by weak tetanization (WT) but not by strong tetanization (ST). (A) Scheme of the placement of recording electrodes in the CA1 region. (B) 4-CPG applied in increasing concentrations does not impair a potentiation induced by a strong tetanization paradigm (ST; 10 bursts of four stimuli at 100 Hz, separated by 200 msec) but was effective (C) if a weak tetanization protocol (WT; 100 Hz, 400-msec duration) was used to generate LTP. Analog traces depict typical responses taken immediately before tetanization (broken line) and 60 min thereafter (solid line). Arrows indicate the time of tetanization and horizontal bars indicate the bath application of 4-CPG.

Figure 2

4-CPG Applied ICV to freely moving animals impaired effectively an LTP induced by a strong tetanization paradigm (ST; 10 bursts of 10 pulses, 100 Hz, interburst interval 10 sec, 0.1-msec duration each stimulus). (A) Schematic diagram of electrode placement for the recording from the CA1 area of the right hemisphere. (B) Time course of the potentiation of the fEPSP slope. Analog traces represent typical recordings from a 4-CPG-treated animal (right) and a control animal (left), taken 5 min (solid line) and 240 min (broken line) after tetanization. The arrow indicates the time of tetanization.

Figure 3

The application of 4-CPG had no influence on behavior in the open field. Bars depict the mean number of crossings (A), grooming bouts (C), and rearings (E), as calculated for each day of testing. In the graphs (B, D, and F, respectively) at the 1-min time courses of the same parameters are given. The only between-group difference that was statistically significant was in the rearing behavior of the 4-CPG group and controls at the seventh minute of day 1 (P < 0.05).

Figure 4

4-CPG only mildly affected spatial learning in the eight-arm RAM. The means of two sessions per day are given. The only difference that was detected concerns the number of reference memory (RM) errors, which was higher on day 1 and day 8 in 4-CPG animals than in controls (C) (P < 0.05). In the schematic of the eight-arm RAM shown in A the dotted lines indicate the triple-beam infrared detector. (BA) Baited arm; (FC) food cup; (IPS) infrared photosensors; (WM) working memory.

Figure 5

The effect of 4-CPG on learning of the SAT was contingent on the difficulty of the particular task configuration. (A–D) Effects of 4-CPG in the more difficult configuration of SAT (dSAT), including a transfer of the experimental animals to another alley after half on the session (20 runs). (A,B) Under these conditions, the ICV application of 4-CPG before the training session prevented the decline of errors on day 2 resulting in percent savings that were not significantly different from zero. Controls, in contrast, displayed a significant retention on the second day. (C,D) The impairment of SAT learning was not state-dependent (sd), as the effects of 4-CPG given before both the training and the retention session (4-CPG/sd) resembled the findings obtained after application of the drug before training depicted above. (E,F) Omission of the transfer (ot) after half of the session (20 runs) resulted in a configuration of SAT that could be acquired more easily (eSAT) as indicated by the higher percent savings as compared with dSAT. This configuration abolished the effect of 4-CPG.