Impaired inhibitory synapse development is suggested to drive neuronal hyperactivity in autism spectrum disorders (ASD) and epilepsy. We propose a novel mechanism by which astrocytes control the development of parvalbumin (PV)-specific inhibitory synapses in the hippocampus, implicating ephrin-B/EphB signaling. Here, we utilize genetic approaches to assess functional and structural connectivity between PV and pyramidal cells (PCs) through whole-cell patch–clamp electrophysiology, optogenetics, immunohistochemical analysis, and behaviors in male and female mice. While inhibitory synapse development is adversely affected by PV-specific expression of EphB2, a strong candidate ASD risk gene, astrocytic ephrin-B1 facilitates PV->PC connectivity through a mechanism involving EphB signaling in PV boutons. In contrast, the loss of astrocytic ephrin-B1 reduces PV->PC connectivity and inhibition, resulting in increased seizure susceptibility and an ASD-like phenotype. Our findings underscore the crucial role of astrocytes in regulating inhibitory circuit development and discover a new role of EphB2 receptors in PV-specific inhibitory synapse development.

抑制性突触发育受损被认为会驱动自闭症谱系障碍 （ASD） 和癫痫中的神经元多动。我们提出了一种新的机制，星形胶质细胞通过该机制控制海马中小白蛋白 （PV） 特异性抑制突触的发育，暗示肝配蛋白-B/EphB 信号传导。在这里，我们利用遗传方法通过全细胞膜片钳电生理学、光遗传学、免疫组织化学分析以及雄性和雌性小鼠的行为来评估 PV 和锥体细胞 （PC） 之间的功能和结构连接。虽然抑制性突触发育受到 EphB2 的 PV 特异性表达的不利影响，EphB2 是一种强候选 ASD 风险基因，而星形胶质细胞肝配蛋白-B1 通过涉及 PV 钮扣中 EphB 信号传导的机制促进 PV->PC 连接。相反，星形胶质细胞肝配蛋白-B1 的缺失降低了 PV->PC 的连接和抑制，导致癫痫发作易感性和 ASD 样表型增加。我们的研究结果强调了星形胶质细胞在调节抑制回路发展中的关键作用，并发现了 EphB2 受体在 PV 特异性抑制突触发育中的新作用。