PI(3)P coordinates SNX17- and SNX27-dependent protein recycling for long-term synaptic plasticity.

Two major protein recycling pathways have emerged as key regulators of enduring forms of synaptic plasticity, such as long-term potentiation (LTP), yet how these pathways are recruited during plasticity is unknown. Phosphatidylinositol-3-phosphate (PI(3)P) is a key regulator of endosomal trafficking and alterations in this lipid have been linked to neurodegeneration. Here, using primary hippocampal neurons, we demonstrate dynamic PI(3)P synthesis during chemical induction of LTP (cLTP), which drives coordinate recruitment of the SNX17-Retriever and SNX27-Retromer pathways to endosomes and synaptic sites. Both pathways are necessary for the cLTP-dependent structural enlargement of dendritic spines and act in parallel by recycling distinct sets of cell surface proteins at synapses. Importantly, preventing PI(3)P synthesis blocks synaptic recruitment of SNX17 and SNX27, decreases cargo recycling, and blocks LTP in cultured neurons and hippocampal slices. These findings provide mechanistic insights into the regulation of endocytic recycling at synapses and define a role for dynamic PI(3)P synthesis in synaptic plasticity.