Protein Synthesis Is Required for the Enhancement of Long-Term Potentiation and Long-Term Memory by Spaced Training

Abstract

Spaced training is generally more effective than massed training for learning and memory, but the molecular mechanisms underlying this trial spacing effect remain poorly characterized. One potential molecular basis for the trial spacing effect is the differential modulation, by distinct temporal patterns of neuronal activity, of protein synthesis-dependent processes that contribute to the expression of specific forms of synaptic plasticity in the mammalian brain. Long-term potentiation (LTP) is a type of synaptic modification that may be important for certain forms of memory storage in the mammalian brain. To explore the role of protein synthesis in the trial spacing effect, we assessed the protein synthesis dependence of hippocampal LTP induced by 100-Hz tetraburst stimulation delivered to mouse hippocampal slices in either a temporally massed (20-s interburst interval) or spaced (5-min interburst interval) fashion. To extend our studies to the behavioral level, we trained mice in fear conditioning using either a massed or spaced training protocol and examined the sensitivity of long-term memory to protein synthesis inhibition. Larger LTP was induced by spaced stimulation in hippocampal slices. This improvement of synaptic potentiation following temporally spaced synaptic stimulation in slices was attenuated by bath application of an inhibitor of protein synthesis. Further, the maintenance of LTP induced by spaced synaptic stimulation was more sensitive to disruption by anisomycin than the maintenance of LTP elicited following massed stimulation. Temporally spaced behavioral training improved long-term memory for contextual but not for cued fear conditioning, and this enhancement of memory for contextual fear was also protein synthesis dependent. Our data reveal that altering the temporal spacing of synaptic stimulation and behavioral training improved hippocampal LTP and enhanced contextual long-term memory. From a broad perspective, these results suggest that the recruitment of protein synthesis-dependent processes important for long-term memory and for long-lasting forms of LTP can be modulated by the temporal profiles of behavioral training and synaptic stimulation.

Distinct kinetics of synaptic structural plasticity, memory formation, and memory decay in massed and spaced learning

“…The spacing effect requires new protein synthesis (14,40). In addition, a recent study has shown that the blockade of protein synthesis in the Fl with anisomycin abolished HOKR adaptation during spaced but not massed training (12).…”

“…We further explored the structural basis of differential memory retention with distinct intervals and examined the correlation between the number of PF-PC synapses and the retention of HOKR gain on day 2. The density of these synapses in the superficial molecular layer of the middle part of the Fl and the adjacent Pfl was measured using the unbiased physical dissector method in M, S 40 , and S 60 mice (Fig. 4).…”

“…The mean of the (4 h) and 1 h after S 60 training with no change at 4 h after training (8 h) and on day 2 (24 h) in Fl (4 h, ***P < 0.001; 5 h, **P < 0.01; n = 300 for all, MWU test). (E) Significant leftward shift of cumulative distributions of PSD length in Fl detected at S 60 4 h (blue filled square; ***P < 0.001, two-sample K-S test) but not at S 60 Fl/Pfl synapse density ratios in the M, S 40 , and S 60 groups exhibited a strong negative correlation with the mean of the HOKR retention ratios (gain increase on day 2/end of the training, r = 0.97, P < 0.001, Pearson correlation; Fig. 4C).…”

Role of Cerebellar Cortical Protein Synthesis in Transfer of Memory Trace of Cerebellum-Dependent Motor Learning

“…In rabbit eyeblink conditioning, infusions of anisomycin into the cerebellar interpositus nuclei depress both the acquisition and retention of the conditioned response (Bracha et al, 1998;Gomi et al, 1999). The role of protein synthesis has been suggested in the memory acquisition induced by the spaced training in the conditioning of the proboscis extension reflex of honey bees (Menzel et al, 2001) and in the contextual learning of fear conditioning in rats (Scharf et al, 2002).…”

Neurogenesis and the spacing effect: Learning over time enhances memory and the survival of new neurons

“…In Drosophila, training with spaced trials extends the memory, which depends on cAMPresponsive element-binding protein (CREB) and protein synthesis (Yin et al 1995). Others find that spaced tetanic stimulation induces a more persistent expression of LTP (Scharf et al 2002) and that the consequences of spaced application of serotonin in Aplysia is more profound than when massed (Mauelshagen et al 1998). Overall, it seems likely that prolonged increase in cell excitability and/or a more refined pattern of activation over time leads to the increase in cell survival in response to learning.…”