Cramming for an exam is an experience familiar to most of us. What might not be obvious is the fact that much of the information learned the night before an exam is forgotten soon afterwards. Retention of learned material for extended periods of time can be modulated by the number of learning trials and by the temporal spacing between trials. Since the latter part of the 19th century, psychologists have observed that multiple training sessions are more effective for producing robust long-term memory (LTM) when they are spaced apart than when they are massed together. What is the molecular basis for this modulation of LTM by trial spacing? One clue comes from the finding that a hallmark of LTM is its requirement for neural protein synthesis. In fruit flies, blocking protein synthesis prevents the enhancement of LTM seen after spaced, but not after massed, training. In mammals the picture is less clear, but there is new evidence that trial spacing can modulate, in a protein-synthesis-dependent manner, not only LTM but also long-term potentiation (LTP) – an enhancement of synaptic strength that is an important regulator of memory processing in the mammalian brain.The hippocampus and amygdala are important for the formation of LTM for contextual fear conditioning (CFC), a task that requires an animal to associate a particular environment (or context) with a harmful experience (e.g. brief footshock). By contrast, LTM for cued fear conditioning (CuFC), in which an animal learns to associate an auditory cue with a harmful experience, is crucially dependent on the amygdala. In a recent study, Scharf et al. showed that spaced training of mice enhanced LTM for CFC, but not for CuFC [1xProtein synthesis is required for the enhancement of LTP and long-term memory by spaced training. Scharf, M.T. et al. J. Neurophysiol. 2002; 87: 2770–2777PubMedSee all References][1]. More importantly, the enhancement of LTM for CFC was blocked by injection of anisomycin, an inhibitor of neural protein synthesis. They also showed that spaced synaptic stimulation of the Schaffer-collateral pathway in area CA1 of hippocampal slices produced larger LTP than massed stimulation. Like LTM following spaced training, Scharf et al. found that maintenance of LTP was more sensitive to disruption by anisomycin following spaced stimulation than following massed stimulation. LTP produced by massed stimulation was still disrupted by anisomycin, but there was significantly more attenuation of the maintenance of LTP after spaced stimulation. These findings provide a striking parallel correlation between LTP and LTM for CFC in mice. They highlight the importance of trial spacing in modulating the efficacy of both LTM and hippocampal LTP, by way of its actions on protein-synthesis-dependent processes. By spacing trials further apart, it is believed that the additional inter-trial time is crucial for optimal recruitment of protein-synthesis-dependent hippocampal pathways that lead to improved LTM. These findings provide an important ‘bridge’ between the invertebrate and mammalian literature, in that they suggest a pivotal role for protein synthesis in regulating synaptic efficacy and LTM following different temporal patterns of behavioural training and synaptic stimulation. Important issues for future exploration include the identification of the proteins responsible for modulating LTM and LTP in a trial-spacing-dependent manner, and the establishment of whether other types of hippocampus- or amygdala-dependent learning and memory are sensitive to trial spacing. In a broader perspective, it is unclear exactly how the temporal characteristics of synaptic activity and behavioural training cause neural circuits to consolidate neural representations of learned information more effectively. Further advances in this area will require continued experimentation using cellular and whole-animal approaches.