The N-methyl-D-aspartate (NMDA)-type glutamate receptor GluRε2 is important for delay and trace eyeblink conditioning in mice

It has been proposed that the N-methyl-D-aspartate (NMDA)-type glutamate receptor (GluR) plays an important role in synaptic plasticity, learning, and memory. The four GluRε (NR2) subunits, which constitute NMDA receptors with a GluRζ (NR1) subunit, differ both in their expression patterns in the brain and in their functional properties. In order to specify the distinct participation of each of these subunits, we focused on the GluRε2 subunits, which are expressed mainly in the forebrain. We investigated delay and trace eyeblink conditioning in GluRε2 heterozygous mutant mice whose content of GluRε2 protein was decreased to about half of that in wild-type mice. GluRε2 mutant mice exhibited severe impairment of the attained level of conditioned response (CR) in the delay paradigm, for which the cerebellum is essential and modulation by the forebrain has been suggested. Moreover, GluRε2 mutant mice showed no trend toward CR acquisition in the trace paradigm with a trace interval of 500 ms, in which the forebrain is critically involved in successful learning. On the other hand, the reduction of GluRε2 proteins did not disturb any basic sensory and motor functions which might have explained the observed impairment. These results are different from those obtained with GluRε1 null mutant mice, which attain a normal level of the CR but at a slower rate in the delay paradigm, and showed a severe impairment in the trace paradigm. Therefore, the NMDA receptor GluRε2 plays a more critical role than the GluRε1 subunit in classical eyeblink conditioning.