Disrupted synaptic inhibition is implicated in neuropsychiatric disorders, yet the molecular mechanisms that shape and sustain inhibitory synapses are poorly understood. Here, we show through rescue experiments performed using Neurexin-3 conditional knockout mice that alternative splicing at SS2 and SS4 regulates the release probability, but not the number, of inhibitory synapses in the olfactory bulb and prefrontal cortex independent of sex. Neurexin-3 splice variants that mediate Neurexin-3 binding to dystroglycan enable inhibitory synapse function, whereas splice variants that don’t allow dystroglycan binding do not. Furthermore, a minimal Neurexin-3 protein that binds to dystroglycan fully sustains inhibitory synaptic function, indicating that trans-synaptic dystroglycan binding is necessary and sufficient for Neurexin-3 function in inhibitory synaptic transmission. Thus, Neurexin-3 enables a normal release probability at inhibitory synapses via a trans-synaptic feedback signaling loop consisting of presynaptic Neurexin-3 and postsynaptic dystroglycan.

突触抑制破坏与神经精神疾病有关，但人们对形成和维持抑制性突触的分子机制知之甚少。在这里，我们通过使用 Neurexin-3 条件性敲除小鼠进行的拯救实验表明，SS2 和 SS4 的选择性剪接调节嗅球和前额叶皮层中抑制性突触的释放概率，而不是数量，与性别无关。介导 Neurexin-3 与肌营养不良聚糖结合的 Neurexin-3 剪接变体能够抑制突触功能，而不允许肌营养不良聚糖结合的剪接变体则不会。此外，与肌营养不良聚糖结合的最小 Neurexin-3 蛋白完全维持抑制性突触功能，表明跨突触肌营养不良聚糖结合对于 Neurexin-3 在抑制性突触传递中的功能是必要且充分的。因此，Neurexin-3 通过由突触前 Neurexin-3 和突触后肌营养不良聚糖组成的跨突触反馈信号环路，在抑制性突触处实现正常释放概率。