It is generally assumed that long-term memory is based on the long-lasting synaptic plasticity accompanied by the formation of new synapses. There is a debate whether LTP per se represents that process. Using stable cultures of rat hippocampal slices, we found recently that a long-lasting (lasting ≥3w) synaptic enhancement coupled with an increase in the number of synapses was established after repeated inductions of, but not a single induction of, LTP. We call this new plastic phenomenon RISE (Repetitive-LTP Induced Synaptic Enhancement) to discriminate it from conventional single LTP. RISE was established after ≥3 inductions of late-phase LTP spaced by proper intervals (3-24h). RISE required the activation of PKA, CaMK and MAPKK. In the developing phase of RISE, Ca2+-permeable AMPA receptors were transiently expressed and their activity was necessary for the establishment of RISE. DNA microarray analysis revealed that the genes up- and down-regulated after the 3rd LTP induction included those of regulatory proteins for actin-cytoskeleton, synaptic scaffold proteins and cell adhesion molecules, confirming that a dynamic structural reorganization leading to synaptogenesis occurred during the development of RISE. We propose that RISE should serve as a useful model system for an in vitro analysis of long-term memory. [J Physiol Sci. 2007;57 Suppl:S19]
