电突触耦合调节哺乳动物大脑皮层兴奋性神经元分化

The neocortex commands all higher-order brain function of mammals, including perception, emotion and cognition; it consists of millions of “functional columns” that are thought to be the basic unit underlying the physiological function of the neocortex. Gap junction plays a crucial role in formation of neocortical functional columns, in which adhesive gap junction between radial glial progenitor and their daughter neurons is one of the first steps that guide development of functional columns in the mammalian neocortex. This is because adhesive gap junction is necessary for newborn neurons migrating along their mother redial glial fiber; however, whether gap junctions between progenitor and progeny possess ion channel function (also called electrical synapses) remained unknown. Our previous study showed that electrical synapses are indeed present between progenitor and progeny in the neocortex immediately after neuronal birth in the ventricular/subventricular zone. Based on this finding, we propose this project. Using multiple electrodes whole-cell electrophysiological recordings together with genetics, super-resolution microscope and cell biology, we will further investigate: (1) electrical synapses between radial glial progenitor and progeny progressively uncouple during neuronal migration; (2) the role of electrical synapses between progenitor and progeny in neuronal differentiation and assembly of neuronal circuit in the neocortex; (3) mechanisms underlying uncoupling of electrical synapses between progenitor and progeny. Results from this study will provide new insights into how electrical synapses between progenitor and progeny instruct formation of functional neocortex in the mammal. Neocortical defect has been linked to many neurological and psychological disorders, including epilepsy, mental retardation, autism and schizophrenia. Thus, our study will also shed light on the underlying pathophysiology of many devastating brain disorders and provide new ideas for early diagnosis and treatment development.

大脑皮层负责哺乳动物的较高级脑功能，包括感觉、情绪和认知；它由成百万个大脑皮层的基本功能单位---功能柱构成。缝隙连接在大脑皮层功能柱形成上发挥极其重要的功能；其中，放射型胶质干细胞和子神经元之间的缝隙连接的黏附作用力是保障功能柱正常形成的第一步，因为它是新生神经元沿着母细胞纤维向大脑皮层迁移所必须的。我们最新研究证实，这种干细胞和子神经元之间的缝隙连接也具有离子通道功能，又称为电突触功能。在此基础上，本课题拟利用多通道膜片钳全细胞记录，结合基因手段、高分辨成像和细胞分子生物学技术，研究：（1）放射型胶质干细胞和子神经元之间的电突触在神经元迁移中的逐渐去耦合；（2）干细胞和子神经元之间的电突触去耦合对神经元分化以及大脑皮层神经环路形成的影响；（3）调控干细胞和子神经元之间的电突触在迁移中的去耦合机制。从而，了解放射型胶质干细胞和子神经元之间的电突触耦合在大脑皮层发育中的生物学意义。

大脑皮层负责哺乳动物的较高级脑功能，包括感觉、情绪和认知；它由成百万个大脑皮层的基本功能单位---功能柱构成。缝隙连接在大脑皮层功能柱形成上发挥极其重要的功能；其中，放射型胶质干细胞和子神经元之间的缝隙连接的黏附作用力是保障功能柱正常形成的第一步，因为它是新生神经元沿着母细胞纤维向大脑皮层迁移所必须的。本课题拟利用多通道膜片钳全细胞记录，结合基因手段、高分辨成像和细胞分子生物学技术，我们研究证实: (1) 这种干细胞和子神经元之间的缝隙连接也具有离子通道功能，又称为电突触功能; (2) 放射型胶质干细胞和子神经元之间的电突触在神经元迁移中的逐渐去耦合；（3）干细胞和子神经元之间的电突触去耦合促进了神经元分化、成熟以及大脑皮层神经环路形成；（3）开发了电突触的临近标记法 (pupylation interacting labeling, PUPIL)，它不但可以标记正在发生的电突触，也能标记发育早期曾经出现的（短暂发生的电突触），但是已经消失的电突触。我们的研究探述了放射型胶质干细胞和子神经元之间的电突触耦合在大脑皮层发育中的生物学意义。