美国斯坦福大学医学院Sergiu P. Pasca研究小组近日取得一项新成果。他们剖析了Timothy 综合征前脑组装体中人类中间神经元迁移的分子基础。该项研究成果于2022年1月5日在线发表在《细胞—干细胞》杂志上。

通过使用由皮质和腹侧前脑类器官整合衍生的前脑组装体，研究人员之前在蒂莫西综合征（Timothy syndrome, TS）中发现了皮质神经元迁移缺陷，这是一种由L型钙通道（LTCC）Cav1.2突变引起的严重的神经发育疾病。在这里，他们发现Cav1.2的急性药理学调节可以调节TS中的中间神经元迁移的跳跃长度，但不是频率。

有趣的是，跳跃长度的缺陷与异常的肌动球蛋白和肌球蛋白轻链（myosin light chain ,MLC）的磷酸化有关，而跳跃频率的缺陷是由增强的γ-氨基丁酸（GABA）敏感性增强驱动的，可通过GABA-A受体拮抗来恢复。最后，研究人员描述了TS中超同步的hCS网络活动，该活动因中间神经元迁移而加剧。综上所述，这些研究揭示了LTCC功能在人类皮质中间神经元迁移和疾病背景下修复缺陷的策略中的复杂作用。

据介绍，中间神经元迁移的缺陷会破坏皮质回路的组装，导致神经精神疾病。

附：英文原文

Title: Dissecting the molecular basis of human interneuron migration in forebrain assembloids from Timothy syndrome

Author: Fikri Birey, Min-Yin Li, Aaron Gordon, Mayuri V. Thete, Alfredo M. Valencia, Omer Revah, Anca M. Paca, Daniel H. Geschwind, Sergiu P. Paca

Issue&Volume: 2022-01-05

Abstract: Defects in interneuron migration can disrupt the assembly of cortical circuits andlead to neuropsychiatric disease. Using forebrain assembloids derived by integrationof cortical and ventral forebrain organoids, we have previously discovered a corticalinterneuron migration defect in Timothy syndrome (TS), a severe neurodevelopmentaldisease caused by a mutation in the L-type calcium channel (LTCC) Cav1.2. Here, we find that acute pharmacological modulation of Cav1.2 can regulate the saltation length, but not the frequency, of interneuron migrationin TS. Interestingly, the defect in saltation length is related to aberrant actomyosinand myosin light chain (MLC) phosphorylation, while the defect in saltation frequencyis driven by enhanced γ-aminobutyric acid (GABA) sensitivity and can be restored byGABA-A receptor antagonism. Finally, we describe hypersynchronous hCS network activityin TS that is exacerbated by interneuron migration. Taken together, these studiesreveal a complex role of LTCC function in human cortical interneuron migration andstrategies to restore deficits in the context of disease.

DOI: 10.1016/j.stem.2021.11.011

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(21)00483-5