Lyu Cheng, Li Zhuoran, Xu Chuanyun, Kalai Jordan, Luo Liqun
Department of Biology and Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA.
Biology Graduate Program, Stanford University, Stanford, CA 94305, USA.
bioRxiv. 2025 Jul 19:2025.03.01.640986. doi: 10.1101/2025.03.01.640986.
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, it remains largely unknown how multiple CSPs work together to assemble a functional circuit. Here, we used synaptic partner matching in the olfactory circuit 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. 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.
大脑的正常功能需要在发育过程中精确组装神经回路。尽管已经鉴定出许多有助于引导轴突到达其靶标的细胞表面蛋白（CSP），但多个CSP如何协同作用以组装功能回路在很大程度上仍然未知。在这里，我们利用嗅觉回路中的突触伙伴匹配来解决这个问题。通过系统地改变单一嗅觉受体神经元（ORN）类型中差异表达的CSP的组合，该ORN类型感知一种抑制雄-雄求偶行为的雄性信息素，我们将其与内源性突触后投射神经元（PN）类型的连接几乎完全切换到一种促进求偶行为的新PN类型。通过这种切换，我们推导了一种组合密码，其中包括介导突触伙伴之间吸引力和非伙伴之间排斥力的CSP。这种解剖学上的切换改变了新PN伙伴的气味反应，并显著增加了雄-雄求偶行为。我们从这种重新布线中归纳出三种操纵策略——增加与旧伙伴的排斥力、减少与新伙伴的排斥力以及与新伙伴匹配吸引力——以成功地将第二种ORN类型重新布线到多种不同的PN类型。这项工作表明，操纵一小部分CSP足以重新指定突触连接，为探索神经系统如何通过回路连接性的变化而进化铺平了道路。
