Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, 94305, USA.
Nat Commun. 2023 Mar 30;14(1):1771. doi: 10.1038/s41467-023-36872-8.
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.
突触抑制紊乱与神经精神疾病有关，但塑造和维持抑制性突触的分子机制还知之甚少。通过使用 Neurexin-3 条件性敲除小鼠进行的挽救实验，我们表明 SS2 和 SS4 的选择性剪接独立于性别调节嗅球和前额叶皮层中抑制性突触的释放概率，但不调节其数量。介导 Neurexin-3 与 dystroglycan 结合的 Neurexin-3 剪接变体可实现抑制性突触功能，而不允许 dystroglycan 结合的剪接变体则不能。此外，与 dystroglycan 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 dystroglycan 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 dystroglycan 组成的突触后反馈信号环在抑制性突触上实现正常的释放概率。
