Tangentially Migrating Neurons During Corticogenesis

描述（由申请人提供）：本提案的长期目标是有助于理解哺乳动物大脑皮层的发育。具体来说，我们将重点放在GABA作为一种“发育性神经递质”上，并建议研究皮层中间神经元对GABA敏感性的发展，因为它们从腹侧端脑切向皮层的指定位置迁移。最重要的假设是，切向迁移的细胞在对GABA的反应以及GABAA受体亚基的表达方面具有异质性和动态性，这些动态特性反映了它们受外部信号调节的迁移倾向。目前有大量证据表明，含有gaba的皮层中间神经元起源于神经节隆起（GE），并沿切向迁移途径进入皮层。在皮质发生开始时，ge来源的细胞聚集在边缘区（第1层），而后来产生的细胞进入较低的中间区。然而，我们对切向迁移神经元的功能发育知之甚少。在这个项目中，我们的问题是：(1)切向迁移细胞在其迁移路线上的哪些点获得对GABA的敏感性？(2)切向迁移的细胞对GABA是否表现出不同的反应特征？它们是否表达不同的GABAA受体亚基？(3)这些差异是否与切向迁移细胞的组织起源、免疫组织化学特性有关？(4) GABA是否调节皮层发育过程中的切向迁移？(5)其机制是否涉及切向迁移细胞表达的GABA受体的激活和细胞外环境中GABA的环境水平？(6) GABAA受体的表达是内在程序化的还是受切向迁移调节因素的影响？对神经元迁移的兴趣从未如此强烈，因为最近的研究表明，人类几种自然发生的遗传缺陷中存在迁移异常。对上述问题的回答将有助于阐明许多突出和紧迫的问题，包括切向迁移、皮层中间神经元的发育和一般的皮层发育。

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to contribute to understanding the development of the mammalian cerebral cortex. Specifically, we focus on GABA as a "developmental neurotransmitter" and propose to study the development of sensitivity to GABA in cortical interneurons as they migrate tangentially from the ventral telencephalon to their destined positions in the cortex. The overriding hypothesis is that the tangentially migrating cells are heterogeneous and dynamic in their response profiles to GABA as well as expression of GABAA receptor subunits, and that these dynamic properties reflect their migratory disposition that is subject to regulation by extrinsic cues. There is now abundant evidence that GABA-containing cortical interneurons originate in the ganglionic eminence (GE) and follow tangential migratory routes to enter the cortex. GE-derived cells at the onset of corticogenesis populate the marginal zone (layer 1) while later generated cells enter the lower intermediate zone. However, little is known about their functional development of tangentially migrating neurons. In this project, we ask: (1) At what points along their migratory routes do tangentially migrating cells acquire sensitivity to GABA? (2) Do tangentially migrating cells display different response profiles to GABA and do they express different GABAA receptor subunits? (3) Are these differences related to the histogenetic origins, immunohistochemical identities of tangentially migrating cells? (4) Does GABA regulate tangential migration during cortical development? (5) Does the mechanism involve activation of GABA receptors expressed by tangentially migrating cells and ambient levels of GABA in the extracellular milieu? (6) Is the expression of GABAA receptors programmed intrinsically or is it influenced by factors that regulate tangential migration? Interest in neuronal migration has never been greater, as recent investigations have implicated migration abnormalities in several naturally occurring genetic defects in humans. Answers to the above questions will contribute toward elucidating many outstanding and pressing issues about tangential migration, the development of cortical interneuons and cortical development in general.