The fundamental observation that the temporal spacing of learning episodes plays a critical role in the efficiency of memory encoding has had little effect on either research on long-term potentiation (LTP) or efforts to develop cognitive enhancers. Here we review recent findings describing a spaced trials phenomenon for LTP that appears to be related to recent evidence that plasticity thresholds differ between synapses in the adult hippocampus. Results of tests with one memory enhancing drug suggest that the compound potently facilitates LTP via effects on 'high threshold' synapses and thus alters the temporally extended timing rules. Possible implications of these results for our understanding of LTP substrates, neurobiological contributors to the distributed practice effect, and the consequences of memory enhancement are discussed. This article is part of a Special Issue entitled 'Cognitive Enhancers'.
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