失调的神经突起生长和突触形成是许多精神障碍的根源，也是 Wolfram 综合征表现的原因之一。WFS1 基因缺陷是否以及如何影响突触形成仍不清楚。通过在脑器官中模拟人类大脑发育，WFS1 缺陷的脑器官不仅复制了 WS 患者中的神经元丢失，而且表现出明显的突触形成和功能障碍，并伴随着减少的星形胶质细胞。神经元的 WFS1 缺陷自主地延迟神经元分化，并改变了与精神障碍有关的基因的表达，导致神经突起生长和突触形成受到影响，胞质钙离子水平升高。有趣的是，星形胶质细胞中的 WFS1 缺陷通过 NF-κB 活化降低了谷氨酸转运蛋白 EAAT2 的表达，并诱导过度释放谷氨酸。当与野生型神经元共培养时，WFS1 缺陷的星形胶质细胞导致神经元的神经突起生长受损和胞质钙离子水平升高。重要的是，Riluzole 治疗可以有效逆转 WFS1 缺陷的脑器官中受损的突触形成和功能，并且可以通过恢复星形胶质细胞中的 EAAT2 表达来逆转 WFS1 缺陷对神经突起生长的影响。此外，Riluzole 可以挽救 Wfs1 条件性基因敲除小鼠中强制游泳测试中的抑郁行为和新物体测试和水迷宫测试中受损的识别和空间记忆。总的来说，我们的研究提供了关于 WFS1 缺陷如何影响突触形成和功能的新见解，并提供了治疗该疾病的策略。©2023年作者。

Dysregulated neurite outgrowth and synapse formation underlie many psychiatric disorders, which are also manifested by wolfram syndrome (WS). Whether and how the causative gene WFS1 deficiency affects synapse formation remain elusive. By mirroring human brain development with cerebral organoids, WFS1-deficient cerebral organoids not only recapitulate the neuronal loss in WS patients, but also exhibit significantly impaired synapse formation and function associated with reduced astrocytes. WFS1 deficiency in neurons autonomously delays neuronal differentiation with altered expressions of genes associated with psychiatric disorders, and impairs neurite outgrowth and synapse formation with elevated cytosolic calcium. Intriguingly, WFS1 deficiency in astrocytes decreases the expression of glutamate transporter EAAT2 by NF-κB activation and induces excessive glutamate. When co-cultured with wildtype neurons, WFS1-deficient astrocytes lead to impaired neurite outgrowth and increased cytosolic calcium in neurons. Importantly, disrupted synapse formation and function in WFS1-deficient cerebral organoids and impaired neurite outgrowth affected by WFS1-deficient astrocytes are efficiently reversed with Riluzole treatment, by restoring EAAT2 expression in astrocytes. Furthermore, Riluzole rescues the depressive-like behavior in the forced swimming test and the impaired recognition and spatial memory in the novel object test and water maze test in Wfs1 conditional knockout mice. Altogether, our study provides novel insights into how WFS1 deficiency affects synapse formation and function, and offers a strategy to treat this disease.© 2023. The Author(s).