Modeling disrupted synapse formation in wolfram syndrome using hESCs-derived neural cells and cerebral organoids identifies Riluzole as a therapeutic molecule

Autor: Fei Yuan, Yana Li, Rui Hu, Mengting Gong, Mengyao Chai, Xuefei Ma, Jiaxue Cha, Pan Guo, Kaijiang Yang, Mushan Li, Minglu Xu, Qing Ma, Qiang Su, Chuan Zhang, Zhejin Sheng, Heng Wu, Yuan Wang, Wen Yuan, Shan Bian, Li Shao, Ru Zhang, Kaicheng Li, Zhen Shao, Zhen-Ning Zhang, Weida Li
Rok vydání: 2023
Předmět:
Zdroj: Molecular Psychiatry. 28:1557-1570
ISSN: 1476-5578
1359-4184
Popis: 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.
Databáze: OpenAIRE
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