Dual endomembrane recycling pathways function in parallel to support synapse maintenance and plasticity.

The SNX27-Retromer and more recently discovered SNX17-Retriever complexes are key drivers in recycling internalized cargoes back to the cell surface in eukaryotic cells, but the extent to which these pathways have unique or redundant roles in neurons is not known. Here, we show similar, but non-overlapping, roles of the SNX17-Retriever and SNX27-Retromer pathways in the maintenance and plasticity of excitatory synapses. We find that in vivo disruption of either pathway in developing rats leads to a marked loss of excitatory synapses in CA1 pyramidal neurons, a phenotype that is recapitulated in cultured hippocampal neurons. Further analysis in cultured neurons confirms that SNX17 and SNX27 colocalize prominently with each other and Retriever/Retromer in early endosomes, indicating a largely shared cellular localization of the two pathways. Interestingly, coordinate disruption of both pathways produced an additive loss of excitatory synapses, suggesting parallel roles in synapse maintenance. We further show that certain cargoes are specific for each pathway and that both recycling pathways are essential for numerous forms of synaptic plasticity, including long-term potentiation (LTP), long-term depression (LTD), and homeostatic synaptic scaling. Together, our results support a model where the SNX17-Retriever and SNX27-Retromer pathways function largely in parallel at synapses, with their combinatorial action a key requirement for long-lasting forms of synaptic plasticity.