Altered balance of excitatory and inhibitory learning in a genetically modified mouse model of glutamatergic dysfunction relevant to schizophrenia

David J Sanderson,David M Bannerman,Aletheia Lee,Paul J Harrison,Peter H Seeburg,Rolf Sprengel

doi:10.1038/s41598-017-01925-8

Abstract

The GluA1 AMPAR subunit (encoded by the Gria1 gene) has been implicated in schizophrenia. Gria1 knockout in mice results in recently experienced stimuli acquiring aberrantly high salience. This suggests that GluA1 may be important for learning that is sensitive to the temporal contiguity between events. To test this, mice were trained on a Pavlovian trace conditioning procedure in which the presentation of an auditory cue and food were separated by a temporal interval. Wild-type mice initially learnt, but with prolonged training came to withhold responding during the trace-conditioned cue, responding less than for another cue that was nonreinforced. Gria1 knockout mice, in contrast, showed sustained performance over training, responding more to the trace-conditioned cue than the nonreinforced cue. Therefore, the trace-conditioned cue acquired inhibitory properties (signalling the absence of food) in wild-type mice, but Gria1 deletion impaired the acquisition of inhibition, thus maintaining the stimulus as an excitatory predictor of food. Furthermore, when there was no trace both groups showed successful learning. These results suggest that cognitive abnormalities in disorders like schizophrenia in which gluatamatergic signalling is implicated may be caused by aberrant salience leading to a change in the nature of the information that is encoded.

Highlights

It has been suggested that the positive, psychotic symptoms in disorders like schizophrenia, such as delusions, arise as a result of the aberrant or inappropriate assignment of salience to stimuli[1]
We investigated the performance of Gria1−/− mice on an appetitive Pavlovian discrimination procedure in which food was presented after the reinforced cue (CS+), but not after the another, nonreinforced cue (CS−)
In order to investigate temporal aspects of associative learning and aberrant salience in a mouse model of glutamatergic dysfunction that is relevant to schizophrenia, we examined trace conditioning in Gria1−/− mice

Summary

Introduction

It has been suggested that the positive, psychotic symptoms in disorders like schizophrenia, such as delusions, arise as a result of the aberrant or inappropriate assignment of salience to stimuli[1]. In normal animals the reduction in attention to recently experienced stimuli reduces the likelihood that associations will form between stimuli that, presented in close temporal proximity, are not temporally contiguous. In Gria1−/− mice the prolonged attention that is paid to recently presented stimuli might increase the likelihood that temporally separated events will become associated, leading to aberrant learning[19]. This prediction was tested by assessing the performance of Gria1−/− mice on an appetitive Pavlovian trace conditioning procedure in which there was temporal discontiguity between the conditioned stimulus (CS) and the outcome (food). While normal animals can effectively learn to use cues in their environment to predict when something will happen, and when something is not going to happen based on temporal discontiguity, this ability is diminished in Gria1−/− mice

Methods

Results

Conclusion