Rewiring an olfactory circuit by altering the combinatorial code of cell-surface proteins.

Proper brain function requires the precise assembly of neural circuits during development. Despite the identification of many cell-surface proteins (CSPs) that help guide axons to their targets(1,2), it remains largely unknown how multiple CSPs work together to assemble a functional circuit. Here, we used synaptic partner matching in the Drosophila olfactory circuit(3,4) to address this question. By systematically altering the combination of differentially expressed CSPs in a single olfactory receptor neuron (ORN) type, which senses a male pheromone that inhibits male-male courtship, we switched its connection from its endogenous postsynaptic projection neuron (PN) type nearly completely to a new PN type that promotes courtship. From this switch, we deduced a combinatorial code including CSPs that mediate both attraction between synaptic partners and repulsion between non-partners(5,6). The anatomical switch changed the odor response of the new PN partner and markedly increased male-male courtship. We generalized three manipulation strategies from this rewiring-increasing repulsion with the old partner, decreasing repulsion with the new partner, and matching attraction with the new partner-to successfully rewire a second ORN type to multiple distinct PN types. This work demonstrates that manipulating a small set of CSPs is sufficient to respecify synaptic connections, paving ways to explore how neural systems evolve through changes of circuit connectivity.