The role of hippocampal glutamate receptor-A-dependent synaptic plasticity in conditional learning: the importance of spatiotemporal discontiguity

Abstract

Gene-targeted mice lacking the AMPA receptor subunit glutamate receptor-A (GluR-A or GluR1) and mice with cytotoxic hippocampal lesions were compared with wild-type and sham-operated controls, respectively, on a conditional learning task using an elevated T-maze. Floor inserts (white perspex vs wire mesh) provided a conditional cue indicating in which goal arm a food reward was to be found. The relationship between the floor insert and the rewarded goal arm was constant throughout the experiment. Both lesioned and knock-out mice were able to acquire the task if the floor inserts extended throughout the entire maze, including the start arm and both goal arms. In contrast, both lesioned and knock-out mice were unable to acquire the task if the floor inserts were only present in the start arm of the maze. The absence of the conditional cue (the floor insert) at the time when the place-reward association was experienced thus critically determined whether or not the mice were impaired. We suggest that hippocampal GluR-A-dependent synaptic plasticity contributes to a memory system in rodents for encoding both the spatial and temporal contexts (the where and the when) associated with a particular event.

Figure 1.

Mice with hippocampal lesions and GluR-A^-/- mice are impaired on a conditional version of the T-maze task in which floor inserts located in the start arm of the maze act as conditional cues, indicating which goal arm is to be rewarded. Mean percentage of correct responses ± SEM (untransformed, 10 trials per block) for mice with cytotoxic hippocampal lesions (white squares) or sham-operated controls (white circles) (A) and GluR-A^-/- mice (black squares) and wild-type controls (white circles) (B). During the last block of 10 trials of each experiment, the reward was delivered only after the animal had made a choice. Where error bars appear to be absent, the error is too small to be visible.

Figure 2.

Mice with hippocampal lesions and GluR-A^-/- mice are impaired on a discrete trial, rewarded alternation (spatial nonmatching to place) task on the elevated T-maze (no floor inserts present). Mean percentage of correct responses ± SEM of 20 trials for experiment 1 (left) and experiment 3 (center), sham-operated controls (white bar) and mice with cytotoxic hippocampal lesions (black bar), and experiment 4 (right), wild-type controls (white bar) and GluR-A^-/- mice (gray bar).

Figure 3.

Wild-type and GluR-A^-/- mice acquire a simple discrimination using floor inserts located in the goal arms of the maze at the same rate. Mean percentage of correct responses ± SEM (10 trials per block) for GluR-A^-/- mice (black squares) and wild-type controls (white circles).

Figure 4.

Mice with hippocampal lesions and GluR-A^-/- mice are able to acquire a conditional version of the T-maze task in which floor inserts extending throughout the entire maze (the start arm and both goal arms) act as conditional cues, indicating which goal arm is to be rewarded. Mean percentage of correct responses ± SEM (10 trials per block) for mice with cytotoxic hippocampal lesions (white squares) or sham-operated controls (white circles) (A) and GluR-A^-/- mice (black squares) and wild-type controls (white circles) (B). During the last block of 10 trials of each experiment the reward was delivered only after the animal had made a choice. Where error bars appear to be absent, the error is too small to be visible.

Figure 5.

Photomicrographs of coronal sections taken from a sham-operated control animal (left) and a representative (median for size) hippocampal-lesioned mouse (right).