Synaptic plasticity is important for learning and memory, and requires the regulated movement of neurotransmitter receptors in and out of the synaptic membrane during long-term potentiation (LTP) and long-term depression (LTD). This trafficking is controlled by the regulation of intracellular signalling, but the mechanisms that coordinate these events are not fully understood. Owing to their distribution patterns at the plasma membrane and intracellular organelles, specific phosphoinositides and their interacting factors could provide such a link. One of these is adaptor protein containing PH domain, PTB domain and leucine zipper motif 1 (APPL1), and on page , Mónica Fernández-Monreal, Carla Sánchez-Castillo and José Esteban investigate its role during synaptic plasticity. They observed that APPL1 is required for certain types of synaptic plasticity that involve phosphoinositide 3-kinase (PI3K) signalling, irrespective of their synaptic outcome (LTP or LTD). Mechanistically, the authors demonstrate that APPL1 is specifically involved in the activation of the PI3K–Akt pathway upon LTP induction and is likely to act upstream of Akt activation. Interestingly, truncation experiments show that the PH domain of APPL1, and thus possibly its membrane association, is responsible for its role in LTP. Based on these data, the authors propose that APPL1 mediates forms of synaptic plasticity depending on the downstream intracellular signalling pathways activated and that it provides a molecular link between them.
