大脑皮质抑制性神经环路的发育及其基因调控

Cortical inhibitory circuits are comprised of a heterogeneous population of interneurons that release GABA onto pyramidal neurons (the principal cells of the neocortex). It is being recognized that cortical interneurons through their maintenance of the excitatory/inhibitory balance in the cerebrum are central to the normal function of the nervous system. In addition, cortical interneurons have been implicated in psychiatric and neurological disorders including epilepsy, schizophrenia, bipolar disorders and autism. The embryonic basal telencephalon primarily consists of the medial, lateral and caudal ganglionic eminence (MGE, LGE and CGE respectively). Recent studies suggest that the MGE and CGE produce the vast majority of cortical interneurons. However, it remains unknown whether the LGE also generates a subpopulation of interneurons for the cerebral cortex, and whether primate cortical interneurons are mainly derived from the embryonic basal telencephalon. Aim 1 will address these important gaps in our understanding of the development of cortical interneurons in rodents. Our preliminary results suggest that the LGE also generates some Sp8+/Coup-TFII+ cortical interneurons. Aim 2 will explore the function role of Sp8 and Coup-TFII in the development of cortical interneurons using genetic approaches. In addition, the origin, evolution and classification of interneurons in the primate neocortex remain highly controversial. These controversies are addressed by work proposed in Aim 3 and 4. Finally, in Aim5, we wish to clarify whether the failure to generate or correctly specify specific interneuronal subtypes is the primary etiology for autism (with epilepsy), one of the most devastating developmental brain disorders. If so, cortical interneurons although representing only 20% of the neurons within the cerebral cortex are a particularly attractive target for therapy. If we can understand how this population is generated in human brains, we will take the first step towards assessing whether we can use cell therapies to ameliorate these psychiatric and neurological disorders associated with cortical interneuron dysfunction.

神经系统功能的正常发挥依赖大脑皮质兴奋和抑制的动态平衡。虽然抑制性中间神经元只占皮质神经元总数的20%，但它们与投射神经元所形成的神经环路对维持这一动态平衡起着不可或缺的作用，这也是情感和记忆等高级神经活动的结构基础。近年来发现许多精神神经疾病，如癫痫、自闭症、双向情感障碍及精神分裂症等，与中间神经元发生发育的异常密切相关。脑内中间神经元的起源在啮齿类尚未完全明了，在灵长类则更加知之甚少。本项目拟着重解决以下问题：1. 探讨小鼠大脑皮质中间神经元是否也来自LGE；2. 阐明转录因子Sp8和Coup-TFII对皮质中间神经元发育的调控作用；3. 阐明灵长类皮质中间神经元的起源部位；4. 阐明正常灵长类皮质中间神经元的分类分布规律；5. 观察小儿自闭症脑内中间神经元可能的异常状况。这些问题的解决将有助于阐明相关神经精神疾病的物质基础，也将为发现新的预防、诊断和治疗手段提供科学依据和新的思路。

中间神经元在大脑皮质的发育和功能中起到至关重要的作用。啮齿类动物几乎所有的大脑皮质中间神经元起源于皮质下基底神经节隆起，然而对于人类和非人灵长类大脑皮质中间神经元的起源却知之甚少。本课题选用猕猴和人胚胎脑组织为研究对象，借助转录因子的表达模式，结合免疫组化学染色、分子生物学等实验技术研究了灵长类大脑皮质中间神经元的起源，并进一步阐明其分布规律。我们发现在发育过程中猕猴和人前脑内的多个关键转录因子的表达模式与其在啮齿类动物中的表达模式高度相似，其基底神经节可以分为内侧基底神经节隆起、外侧基底神经节隆起和尾侧基底神经节隆起，由基底神经节隆起所产生的中间神经元经切线迁移的方式向大脑皮质迁移。基于大脑皮质中间神经元持续不断的表达转录因子Sox6、CoupTF II和Sp8，并结合细胞迁移和命运分析等方法，发现绝大多数灵长类大脑皮质GABA能中间神经元起源于前脑腹侧的基底神经节隆起。这一研究结果揭示了哺乳动物（啮齿类、非人灵长类以及人类）大脑皮层中间神经元发育过程中的基本规律：大脑皮质的中间神经元均起源于胚胎基底神经节，这是动物在漫长的进化过程中遵循的一个非常保守而重要的规律。在课题进展过程中我们还研究了灵长类纹状体中间神经元的起源，Coup-TFs对嗅球中间神经的调控，转录因子Sp8在脊髓神经元发育过程中的作用，以及胚胎小鼠背侧大脑皮质神经干细胞的可塑性。这一研究将为利用和改变自体神经干细胞治疗神经系统疾病(如精神分裂症、自闭症、智力低下、儿童多动症、帕金森疾病、阿尔海默兹并和脑损伤等）提供实验依据。