To understand how proper circuit formation and function is established in the mammalian brain, it is necessary to define the genes and signaling pathways that instruct excitatory and inhibitory synapse development. We previously demonstrated that the ligand-receptor pair, Sema4D and Plexin-B1, regulates inhibitory synapse development on an unprecedentedly fast time-scale while having no effect on excitatory synapse development. Here, we report previously undescribed synaptogenic roles for Sema4A and Plexin-B2 and provide new insight into Sema4D and Plexin-B1 regulation of synapse development in rodent hippocampus. First, we show that Sema4a, Sema4d, Plxnb1, and Plxnb2 have distinct and overlapping expression patterns in neurons and glia in the developing hippocampus. Second, we describe a requirement for Plexin-B1 in both the presynaptic axon of inhibitory interneurons as well as the postsynaptic dendrites of excitatory neurons for Sema4D-dependent inhibitory synapse development. Third, we define a new synaptogenic activity for Sema4A in mediating inhibitory and excitatory synapse development. Specifically, we demonstrate that Sema4A signals through the same pathway as Sema4D, via the postsynaptic Plexin-B1 receptor, to promote inhibitory synapse development. However, Sema4A also signals through the Plexin-B2 receptor to promote excitatory synapse development. Our results shed new light on the molecular cues that promote the development of either inhibitory or excitatory synapses in the mammalian hippocampus.

为了了解哺乳动物大脑中如何建立正确的电路形成和功能，有必要定义指导兴奋性和抑制性突触发育的基因和信号通路。我们之前证明，配体-受体对 Sema4D 和 Plexin-B1 以前所未有的快时间尺度调节抑制性突触发育，同时对兴奋性突触发育没有影响。在这里，我们报告了 Sema4A 和 Plexin-B2 之前未描述的突触发生作用，并为 Sema4D 和 Plexin-B1 对啮齿动物海马突触发育的调节提供了新的见解。首先，我们证明Sema4a、Sema4d、Plxnb1和Plxnb2在发育中的海马神经元和神经胶质细胞中具有独特且重叠的表达模式。其次，我们描述了抑制性中间神经元的突触前轴突以及兴奋性神经元的突触后树突对 Sema4D 依赖性抑制性突触发育的需求。第三，我们定义了 Sema4A 在介导抑制性和兴奋性突触发育中的新突触发生活性。具体来说，我们证明 Sema4A 通过与 Sema4D 相同的途径（通过突触后 Plexin-B1 受体）发出信号，以促进抑制性突触发育。然而，Sema4A 还通过 Plexin-B2 受体发出信号，促进兴奋性突触发育。我们的结果为促进哺乳动物海马抑制性或兴奋性突触发育的分子线索提供了新的线索。