Many studies have confirmed the time-limited involvement of the hippocampus in mnemonic processes and suggested that there is reorganization of the responsible brain circuitry during memory consolidation. To clarify such reorganization, we chose trace classical eyeblink conditioning, in which hippocampal ablation produces temporally graded retrograde amnesia. Here, we extended the temporal characterization of retrograde amnesia to other regions that are involved in acquisition during this task: the medial prefrontal cortex (mPFC) and the cerebellum. At a various time interval after establishing the trace conditioned response (CR), rats received an aspiration of one of the three regions. After recovery, the animals were tested for their CR retention. When ablated 1 d after the learning, both the hippocampal lesion and the cerebellar lesion group of rats exhibited a severe impairment in retention of the CR, whereas the mPFC lesion group showed only a slight decline. With an increase in interval between the lesion and the learning, the effect of the hippocampal lesion diminished and that of the mPFC lesion increased. When ablated 4 weeks after the learning, the hippocampal lesion group exhibited as robust CRs as its corresponding control group. In contrast, the mPFC lesion and the cerebellar lesion groups failed to retain the CRs. These results indicate that the hippocampus and the cerebellum, but only marginally the mPFC, constitute a brain circuitry that mediates recently acquired memory. As time elapses, the circuitry is reorganized to use mainly the mPFC and the cerebellum, but not the hippocampus, for remotely acquired memory.

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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 GluRepsilon (NR2) subunits, which constitute NMDA receptors with a GluRzeta (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 GluRepsilon2 subunits, which are expressed mainly in the forebrain. We investigated delay and trace eyeblink conditioning in GluRepsilon2 heterozygous mutant mice whose content of GluRepsilon2 protein was decreased to about half of that in wild-type mice. GluRepsilon2 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, GluRepsilon2 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 GluRepsilon2 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 GluRepsilon1 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 GluRepsilon2 plays a more critical role than the GluRepsilon1 subunit in classical eyeblink conditioning.