Hippocampal long-term potentiation (LTP) can be dissociated in early-LTP lasting 4-5 h and late-LTP with a duration of more than 8 h, the latter of which requires protein synthesis and heterosynaptic activity during its induction. Previous studies in vivo have shown that early-LTP in the dentate gyrus can protein synthesis-dependently be transformed (reinforced) into late-LTP by the association of arousing novel environmental stimuli. Here we show that consolidation of spatial memory also reinforces early-LTP in the dentate gyrus. Both memory consolidation and LTP-reinforcement depend on protein synthesis. Four groups of animals were trained by five, seven, eight or 10 trials, respectively, to recognize a fixed pattern of baited holes. The last trial was performed 15 min after tetanus. Errors of long-term reference memory during the last trial were significantly decreased only in the eight-and 10-trial experimental groups compared to pseudo-trained animals. In correlation to this learning effect we found a reinforcement of early-LTP only in these experimental groups compared to controls. The data suggest that the synthesis of new proteins required for spatial reference-memory formation also contributes to LTP maintenance in the hippocampal dentate gyrus.Long-term potentiation (LTP), a widely studied cellular model for learning and memory formation, can-similar to memory forma tion (Flexner et al. 1965;Grecksch and Matthies 1980;Izquierdo et al. 2002)-be dissociated into an early phase and a late phase. We use the terms "early-LTP" for an initial phase of LTP with a 4-5-h duration that is protein synthesis-independent, and "late-LTP" for a late phase that protein synthesis-dependently maintains over more than 8 h. As pointed out by Kelleher III et al. (2004), these temporal phases of LTP were initially described by Krug et al. (1984) and Frey et al. (1988) and were confirmed by others in vivo (Otani and Abraham 1989;Otani and Ben-Ari 1993) and in vitro (Huang et al. 1994). It was shown that this kind of early-LTP is reinforceable in vivo; that is, it can protein synthesisdependently be transformed into late-LTP (Matthies et al. 1986), by a temporal-related second heterosynaptic input (Seidenbecher et al. 1997;Frey et al. 2001;Straube et al. 2003b). The induction of this form of LTP, in contrast to a short-term potentiation (Frey and Morris 1997), sets a tag at the potentiated synapses that then can profit from plasticity-related proteins, the synthesis of which was induced by the modulatory heterosynaptic inputs. Thus, the processing of the newly synthesized plasticity-related proteins by the tagged synapses allows the transformation of early-LTP into late-LTP. This is essential for reinforcement processes. There is a large body of literature reporting that the maintenance of memories also requires heterosynaptic activation (for review, see Bailey et al. 2000). Late-LTP is considered to be related to long-term memory, whereas early-LTP may represent short-term memory traces (Bach et al. 1999;Jones et al. 2001). T...