Birey Fikri, Li Min-Yin, Gordon Aaron, Thete Mayuri V, Valencia Alfredo M, Revah Omer, Paşca Anca M, Geschwind Daniel H, Paşca Sergiu P
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Brain Organogenesis, Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA 94305, USA.
Program in Neurogenetics, Department of Neurology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Cell Stem Cell. 2022 Feb 3;29(2):248-264.e7. doi: 10.1016/j.stem.2021.11.011. Epub 2022 Jan 5.
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) Ca1.2. Here, we find that acute pharmacological modulation of Ca1.2 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 γ-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 interneuron 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.
中间神经元迁移缺陷会破坏皮质回路的组装并导致神经精神疾病。利用通过整合皮质和腹侧前脑类器官衍生的前脑组装体，我们之前在 Timothy 综合征（TS）中发现了一种皮质中间神经元迁移缺陷，TS 是一种由 L 型钙通道（LTCC）Ca1.2 突变引起的严重神经发育疾病。在此，我们发现对 Ca1.2 进行急性药理学调节可调节 TS 中中间神经元迁移的跳跃长度，但不能调节其频率。有趣的是，跳跃长度缺陷与异常的肌动球蛋白和肌球蛋白轻链（MLC）磷酸化有关，而跳跃频率缺陷则由增强的γ-氨基丁酸（GABA）敏感性驱动，并且可以通过 GABA-A 受体拮抗作用恢复。最后，我们描述了 TS 中过度同步的人类皮质脊髓网络活动，这种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中的复杂作用以及在疾病背景下恢复缺陷的策略。
