Brief Communication The cellular mechanisms of memory are modified by experience

The N-methyl-D-aspartate receptor (NMDAR) is thought to be essential for synaptic plasticity and learning. However, recent work indicates that the role of this receptor depends on the prior history of the research subject. For example, animals trained on a hippocampus-dependent learning task are subsequently able to acquire new information in the absence of NMDAR activation. The current experiments were designed to identify the types of experiences that lead to NMDAR-independent learning. Using contextual fear conditioning in mice, we find that NMDAR-independent learning is only observed when (1) animals are trained on the same behavioral task and (2) initial learning is successfully encoded into long-term memory. [Supplemental material is available for this article.] The cellular and molecular basis of memory has been thoroughly characterized in the hippocampus. Research indicates that N-methyl-D-aspartate receptors (NMDARs) mediate learning by increasing calcium influx and initiating intracellular events that lead to gene expression and synaptic strengthening (Morris et al. 1990; Elgersma and Silva 1999). Similar mechanisms are important for learning and plasticity in a number of other brain systems including eyeblink conditioning in the cerebellum, fear learning in the amygdala, goal-directed learning in the striatum, and conditioned taste aversion in the insular cortex (Fanselow and Kim 1994; Rosenblum et al. 1997; Chen and Steinmetz 2000; Yin et al. 2005). As a result, it is widely believed that NMDAR-mediated plasticity is required for learning andmemory. Despite these data, several studies indicate that prior behavioral experience can reduce or eliminate the need for NMDARs during learning. For example, animals trained on a hippocampus-dependent learning task are subsequently able to acquire ne