Protein Kinase C (PKC) and extracellular signal-regulated kinase (ERK) regulate synaptic plasticity and memory. PKC activation enhances long-term potentiation (LTP) in the hippocampal slices. In addition, activation of PKC by phorbol 12,13-diacetate (PDA) induces ERK activation. However, the mechanisms involved in PDA-induced activation of ERK are not well understood. Using hippocampal slices, we report that PDA induces a sustained activation of ERK. PDA-induced sustained ERK activation critically requires protein synthesis as well as transcription, the cellular processes that play crucial roles in long-lasting LTP and memory. In addition, the mammalian target of rapamycin activity is required for PDA-induced sustained ERK activation. Further, we show that growth factor signalling plays a critical role in PDA-induced sustained ERK activation. These results suggest that sustained ERK activation may have an important role in LTP. (C) 2019 Elsevier Inc. All rights reserved.