Dissecting the molecular basis of human interneuron migration in forebrain assembloids from Timothy syndrome
Dissecting the molecular basis of human interneuron migration in forebrain assembloids from Timothy syndrome
复制标题
DOI：
10.1016/j.stem.2021.11.011
复制
发表时间：
2022-02-03
期刊：
影响因子：
23.9
通讯作者：
Pasca, Sergiu P.
中科院分区：
文献类型：
--
作者：
Birey, Fikri;Li, Min-Yin;Pasca, Sergiu P.
中间神经元迁移的缺陷会破坏皮层回路的组装并导致神经精神疾病。使用通过整合皮质和腹侧前脑类器官而衍生的前脑类胶质细胞，我们先前发现了蒂莫西综合征（TS）中的皮质中间神经元迁移缺陷，这是一种由L型钙通道（LTCC）Ca（v）1.2突变引起的严重神经发育疾病。在这里，我们发现，急性药理学调制的Ca（v）1.2可以调节跳跃长度，但不是频率，中间神经元迁移TS。有趣的是，突变长度的缺陷与异常的肌动球蛋白和肌球蛋白轻链（MLC）磷酸化有关，而突变频率的缺陷是由增强的γ-氨基丁酸（GABA）敏感性驱动的，可以通过GABA-A受体拮抗作用恢复。最后，我们描述了超同步hCS网络活动的TS，加剧了神经元间的迁移。总之，这些研究揭示了LTCC功能在人类皮层中间神经元迁移中的复杂作用，以及在疾病背景下恢复缺陷的策略。
Defects in interneuron migration can disrupt the assembly of cortical circuits and lead to neuropsychiatric disease. Using forebrain assembloids derived by integration of cortical and ventral forebrain organoids, we have previously discovered a cortical interneuron migration defect in Timothy syndrome (TS), a severe neurodevelopmental disease caused by a mutation in the L-type calcium channel (LTCC) Ca(v)1.2. Here, we find that acute pharmacological modulation of Ca(v)1.2 can regulate the saltation length, but not the frequency, of interneuron migration in TS. Interestingly, the defect in saltation length is related to aberrant actomyosin and myosin light chain (MLC) phosphorylation, while the defect in saltation frequency is driven by enhanced gamma-aminobutyric acid (GABA) sensitivity and can be restored by GABA-A receptor antagonism. Finally, we describe hypersynchronous hCS network activity in TS that is exacerbated by intemeuron migration. Taken together, these studies reveal a complex role of LTCC function in human cortical interneuron migration and strategies to restore deficits in the context of disease.