Encoding of Contextual Fear Memory Requires De Novo Proteins in the Prelimbic Cortex

BACKGROUND: Despite our understanding of the significance of the prefrontal cortex in the consolidation of long-term memories, its role in the encoding of long-term memories remains elusive. Here we investigated the role of new protein synthesis in the mouse medial prefrontal cortex (mPFC) in encoding contextual fear memory. METHODS: Because a change in the association of messenger RNAs (mRNAs) to polyribosomes is an indicator of new protein synthesis, we assessed the changes in polyribosome-associated mRNAs in the mPFC following contextual fear conditioning (CFC) in the mouse. Differential gene expression in the mPFC was identified by polyribosome profiling (n = 18). The role of new protein synthesis in the mPFC was determined by focal inhibition of protein synthesis (n = 131) and by intraprelimbic cortex manipulation (n = 56) of Homer3, a candidate identified from polyribosome profiling. RESULTS: We identified several mRNAs that are differentially and temporally recruited to polyribosomes in the mPFC following CFC. Inhibition of protein synthesis in the prelimbic (PL) cortex but not in the anterior cingulate cortex region of the mPFC immediately after CFC disrupted encoding of contextual fear memory. Intriguingly, inhibition of new protein synthesis in the PL cortex 6 hours after CFC did not impair encoding. Furthermore, expression of Homer3, an mRNA enriched in polyribosomes following CFC, in the PL cortex constrained encoding of contextual fear memory. CONCLUSIONS: Our studies identify several molecular substrates of new protein synthesis in the mPFC and establish that encoding of contextual fear memories require new protein synthesis in PL subregion of mPFC.