SPATIOTEMPORAL CONTROL OF SYNAPSE ELIMINATION 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 remarkable technological advances have enabled precise control of synaptic activity, methods for structural remodeling of synaptic connections remain limited. Here, we present SynTrogo (Synthetic Trogocytosis), a synthetic molecular approach for modulating synaptic connections. By engineering complementary ligand and receptor proteins, we enabled physical interaction between two defined cell populations in culture, leading to a trogocytosis-like process in which receptor-expressing cells internalized membrane fragments and adjacent cytosolic material from ligand-expressing cells. Leveraging natural proximity of astrocytes to synapses, we applied SynTrogo to hippocampal CA3 neurons and CA1 astrocytes in adult male mice and observed ultrastructural changes at axon-astrocyte interfaces, accompanied by significant reduction in synaptic connectivity. Notably, the remaining synapses exhibited substantial remodeling, including coordinated pre- and post-synaptic structure changes, reorganization of synaptic components and organelles, and enhanced synaptic plasticity and memory. We further advanced this platform by developing an inducible SynTrogo (iSynTrogo) system through integration with the RUSH (Retention Using Selective Hooks) strategy, enabling biotin-dependent membrane presentation of ligands and receptors and thereby achieving temporally controlled synapse elimination with enhanced efficiency via modular signaling components. This platform will greatly advance our understanding of the structure–function relationship in neural circuits and provides a foundation for developing connectome editing platforms.