Calpain-1 (CANP1) has been shown to play a critical role in synaptic plasticity and learning and memory, as its deletion in mice results in impairment in theta-burst stimulation-(TBS) induced LTP and various forms of learning and memory. Likewise, PHLPP1 (aka SCOP) has also been found to participate in learning and memory, as PHLPP1 overexpression impairs hippocampus-dependent learning. We previously showed that TBS-induced LTP was associated with calpain-1 mediated truncation of PHLPP1.To better understand the roles of these 2 genes in synaptic plasticity and learning and memory, we generated a double knockout (DKO) mouse by crossing the parent strains. Surprisingly, DKO mice exhibit normal TBS-induced LTP, and the learning impairments in fear conditioning and novel object or novel location recognition were absent in the DKO mice. Moreover, TBS-induced ERK activation in field CA1 of hippocampal slices, which is impaired in both single deletion mice, was restored in the DKO mice. These results further strengthen the roles of both CANP1 and PHLPP1 in synaptic plasticity and learning and memory, and illustrate the complexities of the interactions between multiple pathways participating in synaptic plasticity.While tremendous progress has been made regarding our understanding of the molecular/cellular mechanisms underlying learning and memory, many questions regarding the roles of various signaling pathways activated during learning remain unanswered Mehta 2015;Tonegawa et al. 2015;Smolen et al. 2016). In particular, while the calcium-dependent protease, calpain, has been proposed to participate in synaptic plasticity and learning and memory many years ago (Lynch and Baudry 1984), its precise contributions are still not clearly understood. This is in part due to the existence in the brain of two major calpain isoforms, calpain-1 (aka, m-calpain) and calpain-2 (aka, m-calpain), and the lack of tools to study their respective functions in synaptic plasticity. Our previous studies have shown that long-term potentiation (LTP) elicited by theta-burst stimulation (TBS), as well as learning of hippocampus-dependent tasks were impaired in calpain-1 knockout (CANP12/2) mice Liu et al. 2016). We also found that these impairments were related to the lack of calpain-1-mediated truncation of the PH domain and Leucine-rich repeat Protein Phosphatase 1 (PHLPP1, aka suprachiasmatic nucleus oscillatory protein (SCOP)) and the resulting stimulation of the extracellular signal-regulated kinase (ERK), which plays an important role in LTP induction and in learning and memory (Wang et al. 2014). On the other hand, calpain-2 activation was found to limit the extent of potentiation in hippocampal slices and learning of hippocampus-dependent tasks (Liu et al. 2016). It has previously been reported that PHLPP1 overexpression impairs learning and memory (Shimizu et al. 2007), suggesting that PHLPP1 could also participate in synaptic plasticity (Shimizu et al. 2010).To further evaluate the role of the calpain-1-mediated truncation of PHLPP1 i...