Plasticity in the entorhinal cortex suppresses memory for contextual fear.

Several studies have delineated a role for the hippocampus in fear conditioning. However, in this task, the role of the entorhinal cortex (EC), the main input-output structure for the hippocampus, is uncertain. The extracellular signal-regulated kinase (ERK) cascade has been shown to be a molecular correlate for long-term memory, and its activity is required for various types of memory storage, including fear memory. In this study, we show that ERK activity in the EC increased 90 min after fear conditioning. Post-training intra-EC infusion of ERK cascade inhibitors (PD098059, UO126) at 40 min, but not at 10 min, resulted in increased freezing to the context, but not to the tone, during a 48 hr retention test. Interestingly, both PD098059- and UO126-infused animals also demonstrated anticipatory freezing in the context, freezing maximally at the time the shock was given during training. This anticipatory behavior was also seen in naive animals receiving additional training. Together, these results suggest that ERK-mediated plasticity in the EC normally suppresses context-specific fear memory, especially the temporal nature of the freezing response, and that blocking this plasticity mimics the effects of additional training.