Remodeling synaptic connections via engineered neuron-astrocyte interactions

Information flow through synapses in the central nervous system is regulated by both rapid electrochemical activity and slower structural remodeling. While technological advances allow precise manipulation of synaptic activity, methods for structural remodeling remain limited. Here, we present SynTrogo (Synthetic Trogocytosis), a synthetic molecular approach for modulating synaptic connections. By engineering complementary ligand and receptor proteins, we enable physical interaction between two defined cell populations in culture, leading to a trogocytosis-like process in which receptor-expressing cells internalize membrane fragments and adjacent cytosolic material from ligand-expressing cells. Applying SynTrogo to hippocampal CA3 neurons and CA1 astrocytes in adult male mice results in ultrastructural changes at axon-astrocyte interfaces, accompanied by significantly reduced synaptic connectivity. The remaining synapses exhibit coordinated pre- and post-synaptic structural changes and reorganization of synaptic components and organelles, and are associated with enhanced synaptic plasticity and memory performance. These findings suggest that neural circuits can undergo adaptive reshaping under conditions of synaptic reduction and may provide a foundation for editing synaptic architecture with therapeutic potential for connectopathies.