Role of L-type Calcium Channels in Human Interneuron Migration and Integration

摘要 电压门控L型钙通道(LTCCs)基因的变异和突变是其中之一 自闭症谱系障碍、双相情感障碍和自闭症的遗传学研究中最可复制的发现 精神分裂症。这些基因事件导致疾病的机制目前尚不清楚 为人所知。以前的工作表明，这些LTCs在皮质中间神经元中起着关键作用 迁移和功能整合进入大脑皮层回路。在这里，我们建议利用一本小说 人诱导多能干细胞的三维(3D)神经分化 我们开发了产生类似于层叠兴奋性的功能性神经球体 大脑皮层(皮质球体)和大脑皮层下球体分别形成皮质 中间神经元。使用最先进的实时成像，转录分析，基因工程， 药理学和电生理学方法，我们计划组装两个区域的人类 前脑结构(丘脑-兴奋性/苍白球下-抑制)，并探讨其功能作用 皮层中间神经元迁移和功能性突触整合中的LTCCs突变。 好了！

ABSTRACT Gene variants and mutations in voltage-gated L-type calcium channels (LTCCs) genes are among the most replicable findings in genetic studies of autism spectrum disorders, bipolar disorder and schizophrenia. The mechanisms by which these genetic events lead to disease are not currently known. Previous work has indicated that these LTCss play a critical role in cortical interneuron migration and functional integration into cortical circuits. Here, we propose to leverage a novel tridimensional (3D) neural differentiation of human induced pluripotent stem cells (hiPSC) that we developed to generate functional neural spheroids resembling the laminated excitatory cerebral cortex (pallial spheroids) and, separately, subpallial spheroids giving rise to cortical interneurons. Using state-of-the-art live imaging, transcriptional profiling, genetic-engineering, pharmacology and electrophysiological methods, we plan to assemble two-region human forebrain structures (pallial-excitatory/subpallial-inhibitory) and investigate the functional role of LTCCs mutations in migration and functional synaptic integration of cortical interneurons. !