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Metaplasticity: tuning synapses and networks for plasticity
Wickliffe C. Abraham

Abstract | 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 tohelp 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.
Long-term potentiation
(LTP). A long-lasting and activity-dependent increase insynaptic efficacy. Canonically it requires activation of the NMDAR subtype of glutamate receptors; however, different forms of LTP caused by the activation of other receptor subtypes also occur.

Long-term depression
(LTD). The converse of LTP: in LTD there is a long-lasting and activity-dependent decrease in synaptic efficacy.

Excitotoxicity
Cellular toxicity involving the activation ofglutamate receptors in the CNS. Excessive activation of these receptors by high concentrations of glutamate or by neurotoxins leads to cell death.

Tetanus
A bout of HFS used to elicit activity-dependent synaptic plasticity. The frequency and duration of the stimulation varies across protocols. Department of Psychology and the Brain Health and Repair Research Centre, University of Otago, BOX56, Dunedin, 9054, New Zealand. e-mail: cabraham@psy.otago.ac.nz doi:10.1038/nrn2356 Published online 10 April 2008

The ability of neurons to modify their structure and function as a result of activity is critical for normal development, learning and responding to brain damage and neurological disease. At the synaptic level, neural activity can generate persistent forms of synaptic plasticity,such as long-term potentiation (LTP) and long-term depression (LTD). There is now a wealth of data indicating that LTP and LTD mechanisms are used to retain new information in activated networks of neurons1,2. Safeguards must therefore be in place to prevent the saturation of LTP or LTD, which could ultimately compromise the ability of networks to discriminate events and store information and, inthe case of extreme levels of LTP, lead to excitotoxicity. How is the proper balance of LTP and LTD maintained? Various intercellular signalling molecules — including catecholamines, GABA (γ-aminobutyric acid), acetylcholine, cytokines and hormones — directly regulate the degree of LTP and LTD that can be induced. However, a different kind of regulation that persists across time also exists.Here, neural activity at one point in time can change cells or synapses such that their ability to exhibit LTP or LTD after a later bout of activity is altered. This form of plasticity regulation has been termed metaplasticity3,4. The ‘meta’ part of the term reflects the higher-order nature of the plasticity — that is, the plasticity of synaptic plasticity. Essentially, metaplasticity entails achange in the physiological or biochemical state of neurons or synapses that alters their ability to generate synaptic plasticity. A key feature of metaplasticity is that this change outlasts the triggering (priming) bout of activity and persists at least until a second bout of activity induces LTP or LTD (BOX 1). This distinguishes metaplasticity from more conventional forms of plasticity modulationin which the modulating and regulated events overlap in time. Metaplasticity entails an extensive range of mechanisms, many of which overlap with the mechanisms of conventional plasticity. This overlap, plus the fact that plasticity and metaplasticity can be induced simultaneously, poses a considerable challenge for metaplasticity research in terms of experimental design and interpretation....