A particularly interesting property of many glutamatergic synapses is that their strength can be bidirectionally modified; some patterns of stimulation make synapses stronger while others make them weaker. It is generally thought that these dual processes, referred to as long-term potentiation (LTP) and long-term depression (LTD), respectively, contribute to memory storage. Understanding the biochemical events that determine whether the synapse gets stronger or weaker has been an important goal.

It now appears likely that both LTP and LTD are triggered by the same second messenger, Ca2+, and that what determines whether LTP or LTD occurs is the level of Ca2+. Early experiments by Lynch et al.(1983) showed that LTP induction could be blocked by intracellular Ca2+ chelators, suggesting that an activity-dependent elevation of intracellular Ca2+ triggers LTP. But which second messenger triggers LTD? The proposal that LTD is also triggered by Ca2+(Lisman, 1989) was based on the following line of reasoning. One form of LTD that works particularly well in vivo is a heterosynaptic process; the LTP induced by activating one set of synapses induces LTD (technically termed depotentiation) at inactive synapses. The weakened synapses can be quite distant, making it unlikely that what carries the message to them is a diffusible substance. It seemed more plausible that the message is carried by the spread of the depolarization produced by the active synapses. This depolarization could produce Ca2+ elevation at distant synapses by activating voltagedependent Ca2+ channels. The resulting Ca2+ elevation would be smaller than at active synapses where Ca2+ entry through NMDA channels is a second source of Ca2+. This line of reasoning suggests that high Ca2+ elevation might trigger LTP, whereas more moderate Ca2+ elevation might trigger LTD.