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Synaptic plasticity is a key component of the learning machinery in the brain. It is vital that such plasticity be tightly regulated so that it occurs to the proper extent at the proper time. Activity-dependent mechanisms that have been collectively termed metaplasticity have evolved to help implement these essential computational constraints. Various intercellular signalling molecules can trigger lasting changes in the ability of synapses to express plasticity; their mechanisms of action are reviewed here, along with a consideration of how metaplasticity might affect learning and clinical conditions.

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Long-term potentiation (LTP) is widely regarded as a memory mechanism, but it is not known whether it can last long enough to underlie very long-term memory. We report that high-frequency stimulation (HFS) paradigms applied to the rat dentate gyrus can elicit stable LTP lasting months and up to at least 1 year. The induction of stable LTP was sensitive to stimulation variables on the day of HFS and was associated with phosphorylation of cAMP response element-binding protein. The maintenance of stable LTP was also experience-dependent, because it was reversed when animals were exposed repeatedly to an enriched environment beginning 14 d post-HFS. However, stable LTP eventually consolidated over time and became resistant to reversal, because exposure to enriched environments 90 d post-HFS failed to influence stable LTP maintenance. Thus, LTP can be shown to meet one of the principal criteria for a very long-term memory storage mechanism. However, under naturalistic environmental conditions, LTP may normally be retained in the hippocampus for only short periods of time.

Long-term depression (LTD) is a lasting decrease in synaptic effectiveness that follows some types of electrical stimulation in the hippocampus. Two broad types of LTD may be distinguished. Heterosynaptic LTD can occur at synapses that are inactive, normally during high-frequency stimulation of a converging synaptic input. Homosynaptic LTD can occur at synapses that are activated, normally at low frequencies. Here we discuss the mechanisms of LTD and their possible relevance to hippocampal function.

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