The standard Morris water maze task tests animals' ability for "reference" memory, which is acquired incrementally over multiple trials and involves information that is constant across trials. Another type of memory supported by the hippocampus is "episodic" memory, which is acquired rapidly with one-trial or one-time experience and involves trial- or event-specific information. It is likely that different mechanisms underlie these two types of declarative memory, although both can be hippocampus dependent. Little is known, however, about underlying differential mechanisms. It has been suggested that the learning rate and the number of unambiguous patterns are greater in a network with bidirectional modifiability of synaptic strength than in a network with unidirectional modifiability. For instance, the information storage efficiency of a network with only LTP capability would be lower than that of a network with both LTP and LTD (long-term depression) capability. There is also, however, a hypothesis that only LTP is important for memory and LTD serves an "antimemory" role. We previously generated a conditional knockout mouse in which the deletion of a protein phosphatase, calcineurin, is restricted to the adult forebrain and showed these mice are impaired in LTD but not in LTP. The mutant mice are normal in the acquisition and retrieval of spatial reference memory but are specifically impaired in two tasks for spatial episodic memory: the delayed-matching-to-place (DMP) version of the Morris water maze and the working memory version of Olten's eight-arm radial maze. These results support the notion that a network with bidirectional modifiability of synaptic strength plays a crucial role in the acquisition of episodic memory, while it is dispensable for reference memory. The results also indicate that LTD, along with LTP, constitutes the basis for effective memory systems.

During the past year, we also tested the hypothesis that a recurrent network with robust synaptic modifiability like the one in area CA3 of the hippocampus plays a crucial role in the rapid encoding of a novel event. For this purpose, we generated a knockout mouse (CA3-NR1 KO) in which the deletion of the NR1 gene is restricted to the CA3 pyramidal cells of an adult mouse. These mice are impaired in the spatial DMP task when the platform is placed in a novel location, but are normal when the platform location employed a few days earlier is reused. This behavioral deficit is highly specific, in that the mutants are normal in the acquisition of spatial reference memory. We monitored the activities of the pyramidal cells in CA1, the area downstream of CA3 and the site for the hippocampal output, before and after the animals entered a novel space from a familiar space (a collaboration with Matthew Wilson). The specificity of tuning in the mutants was reduced during the first 15 minutes of exploration in the novel space compared to the same period in the familiar space. In contrast, no space shift–associated change of spatial tuning was observed when the mutant mice were returned one day later to the pair of spaces experienced on the previous day. The spatial tuning of CA1 place cells of control animals did not exhibit any space shift–associated changes. These results suggest that CA3 NRs, most probably those in the recurrent network, play a crucial role in rapid hippocampal encoding of a novel encounter and in one-trial- or one-experience-based rapid learning.

• Memory Consolidation
• Memory Recall