Long-term potentiation (LTP) is a long-lasting strengthening of synaptic transmission that is triggered by brief periods of high-frequency synaptic stimulation. Other patterns of stimulation can produce a long-term weakening of synapses, a process termed long-term depression (LTD) or depotentiation. Synapses thus have a stable strength that can be bi-directionally modified in an activity-dependent manner. There are different forms of LTP at different brain synapses. This article focuses on LTP found at glutamatergic synapses in the CA1 region of the hippocampus, the most studied form of LTP. A typical experiment starts by measuring the strength of a group of synapses. This is done by firing a single action potential in some of the axons that enter this region. These axons make synapses with pyramidal cells and generate an excitatory postsynaptic potential (EPSP). The collective strength of the synapses is defined by the magnitude of the average EPSP. LTP is then induced by stimulating the axons to fire at high frequency (typically 100 Hz for 1 s), a stimulus referred to as a tetanus. Remarkably, this brief tetanus causes a long-lasting potentiation of the strength of the synapses. The size of the EPSP typically increases by 50%-100%, but can rise by as much as 800% in some situations. In the brain-slice preparation used for most studies, potentiation persists until the slice is no longer viable (5-12 h). LTP can also be induced in living animals, where it can persist for at least a year (1). The evidence that such changes in synaptic strength are actually involved in memory has strengthened in recent years. Studies have examined the effect of a learning experience on synapses in the hippocampus. Two groups (67, 225) have demonstrated that learning induces an LTP-like process, which reduces the subsequent ability to experimentally induce LTP at these synapses. This occlusion suggests that learning-induced and experimentally-induced potentiation affect the same synaptic process. Other experiments showed that electrically inducing LTP in a large fraction of synapses after learning disrupts memory (24) as would be expected if memory is stored by the pattern of synapses that undergo LTP during learning. Another approach has examined whether the molecular events required for LTP induction occur during learning. The results of these experiments are generally supportive of a linkage. Activation of CaMKII and GluR1 phosphorylation, two events associated with LTP (see later sections) occur during learning (17). Moreover, if LTPassociated changes are prevented (NMDA receptor activation, CaMKII activation, GluR1 insertion), learning is inhibited (60, 189, 217). Finally, recent work shows that procedures that can reverse LTP after learning, can reverse memory (175, 199). Taken together, these observations make a reasonably strong case that at least some kinds of memory are stored by an LTP-like process.
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