Long-lasting forms of synaptic potentiation in the mammalian hippocampus.

I n t r o d u c t i o n Memory storage in the mammalian brain is commonly divided into at least two distinct temporal phases: short-term memory, lasting minutes to hours, and long-term memory, which can persist for days, weeks, or even years (for review, see Polster et al. 1991). Whereas short-term memory requires only covalent modifications of pre existing proteins, long-term memory requires the synthesis of new mRNA and protein (Davis and Squire 1984; Castellucci et al. 1989; Tully et al. 1994). The idea that memory storage in the brain results from activity-dependent changes in synaptic strength was elaborated by Hebb (1949), who proposed that synapses linking two cells could be strengthened if both cells were active simultaneously. The first such Hebbian synapses to be found in the mammalian brain were the connections made by entorhinal perforant path fibers onto dentate granule cells in the hippocampus (Bliss and Lomo 1973). Brief, high-frequency stimulation of this excitatory pathway elicited a long-lasting enhancement of synaptic transmission. This effect, now known as long-term potentiation (LTP), can last for 8 -10 hr in hippocampal slices, and for several days and even weeks in intact animals. LTP has now been shown in all three major monosynaptic excitatory pathways within the hippocampus ( the perforant pathway, mossy fiber pathway, and Schaffer collateral pathway) (Bliss and Collingridge 1993). Hippocampal LTP has a number of properties that make it an attractive model for memory storage. These include associativity, synapse specificity, cooperativity, and persistence (see Bliss and Collingridge 1993 for a more complete description). In this review, we will focus on the long-term maintenance (late phase) of LTP and its underlying mechanisms. We will try to illustrate how pharmacological and molecular biological approaches, some with genetically modified animals, have elucidated some of the mechanisms that contribute to long-term changes in synaptic strength. Most of the experiments that we will discuss use the hippocampal slice preparation, and they focus on synaptic changes occurring over hours. Thus, these changes pertain primarily to the initial phase of the cellular changes that contribute to long-term memory storage. Other, still longer term changes in synaptic strength that may occur over days or weeks can be studied in the intact animal, but these will not be discussed here.