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Trendsetters
Department of Psychology University of Otago Box 56 Dunedin, New Zealand
In this section we feature some of the latest and most striking new findings in physiology, interpreting the term "physiology" in its broadest sense. In each instance, an effort will be made to place the new findings in perspective.
Heinz Valtin
Editor, TRENDSETTERS
It is widely recognized that the efficacy of the synaptic connections between neurons can be rapidly and persistently modified by brief periods of patterned neural activity. Upregulation of synaptic efficacy is termed long-term potentiation (LTP), whereas downregulation is known as long-term depression (LTD). LTP and LTD are believed to be fundamental to storage of memory in the brain and hence learning.
There are numerous outstanding questions regarding LTP and LTD, and one hindrance to answering them has been the difficulty in finding electrical stimulation parameters that induce LTP and LTD reliably across preparations and labs, particularly in vivo. One of the causes for the difficulty is that LTP and LTD are highly regulated functions that depend on the current synaptic "state", as set by ongoing extrinsic influences such as the level of synaptic inhibition, the activity of modulatory afferents such as catecholamines, and the pool of hormones affecting the synapses under study. Recently, it has become clear that the prior history of synaptic activity is an additional variable that influences the synaptic state, and thereby the degree, of LTP or LTD produced by a given experimental protocol. In a sense, then, synaptic plasticity is governed by an activity-dependent plasticity of the synaptic state; such plasticity of synaptic plasticity has been termed "metaplasticity" (1).
Metaplasticity encompasses a range of effects, most of which have been studied at glutamatergic synapses in the hippocampus. The following example illustrates the complexity of metaplasticity: prior (priming) activation of the N-methyl-D-aspartate subtype of glutamate receptors inhibits subsequent LTP induction by synaptic activity but facilitates LTD (1). On the other hand, prior activation of metabotropic glutamate receptors (so called because they couple to second-messenger signaling cascades rather than ion channels) facilitates the induction of LTP at these same synapses (2). In most studies, such metaplasticity lasts tens of minutes to a few hours and is "homosynaptic", i.e., it is observed in the synapses that received the priming stimulation. However, longer-lasting effects that involve even synapses that were not primed may occur if more robust priming stimulation is used (3).
What is the functional significance of metaplasticity? Two likely possibilities are presented here. First, metaplasticity may play an important role in keeping synaptic strengths within a dynamic range that is optimal for the learning process (1). For example, if the induction of LTP were also to promote further LTP at those synapses, the self-perpetuating positive-feedback cycle would lead to a deleterious state of saturated upregulation of synaptic connections; a similar argument would apply to unfettered downregulation by LTD. Such instability would significantly impair the learning capacity of a network. Metaplasticity can stabilize the behavior of plastic synapses, however, by modifying the thresholds for LTP and LTD according to the history of prior activity. Thus metaplasticity can make it difficult for previously potentiated synapses to express further LTP, thereby braking the development toward a saturated state, and vice versa for LTD.
A second important function of metaplasticity may be to provide a mechanism for integrating synaptic events across periods of time orders of magnitude longer than the tens of milliseconds typical of temporal summation of synaptic potentials. Frey and Morris (3), for example, have shown that the persistence of LTP of weakly activated synapses can be greatly extended if induced during a time of new protein synthesis that has been triggered previously by strong synaptic activation. These recent data illustrate one intriguing way that a neuron can integrate synaptic signals over tens of minutes, and they emphasize the important point that the nature of plasticity (in this instance, its persistence) is very sensitive to the internal milieu as established by prior synaptic activity.
In summary, metaplasticity can potently influence information storage properties at a synaptic level. The task now is to determine the mechanisms underlying various metaplasticity phenomena and to understand how they influence the ability of larger neuronal networks to process information.
References
| Occasionally, the Editor of the Trendsetters section invites contributions from the authors of published scientific articles that have been identified as being of special interest. All précis to Trendsetters are by invitation only. |
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  S. Sajikumar, Q. Li, W. C. Abraham, and Z. C. Xiao Priming of short-term potentiation and synaptic tagging/capture mechanisms by ryanodine receptor activation in rat hippocampal CA1 Learn. Mem., February 17, 2009; 16(3): 178 - 186. [Abstract] [Full Text] [PDF]
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 M. B. Iyer, N. Schleper, and E. M. Wassermann Priming Stimulation Enhances the Depressant Effect of Low-Frequency Repetitive Transcranial Magnetic Stimulation J. Neurosci., November 26, 2003; 23(34): 10867 - 10872. [Abstract] [Full Text] [PDF]
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 A. Xie, J. B. Skatrud, D. C. Crabtree, D. S. Puleo, B. M. Goodman, and B. J. Morgan Neurocirculatory consequences of intermittent asphyxia in humans J Appl Physiol, October 1, 2000; 89(4): 1333 - 1339. [Abstract] [Full Text] [PDF]
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