Molecular mechanisms for calcium-mediated refinement of competitive synaptic wiring in the brain

钙介导的大脑竞争性突触接线细化的分子机制

基本信息

批准号：
19100005
负责人：
WATANABE Masahiko
金额：
$ 74.8万
依托单位：
Hokkaido University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (S)
财政年份：
2007
资助国家：
日本
起止时间：
2007 至 2011
项目状态：
已结题

项目摘要

Synaptic circuits in neonates are characterized by excess, overlapping and entangled wiring. These immature circuits are refined into functional and mature ones through use-dependent and activity-dependent strengthening and weakening/elimination of immature synapses. Through this process, almost all of higher brain functions develop robustly during sensitive or critical period of early postnatal life, including cognition, language, music performance, sports, intelligence, thought, personality, and sociality in the case of human beings. Now we understand that the activity dependent synaptic circuit development is facilitated by glutamate receptor activation and subsequent calcium influx into postsynaptic neurons. However little is known about how calcium influx regulates competitive synaptic development. In this research project, we aimed to clarify this issue by focusing on calcium-dependent and-independent mechanisms using neuroanatomical, electrophysiological, and developmental biological technologies. Through this research project, I clarified that P/Q-type calcium channels promote the development and maturation of climbing fiber innervation to Purkinje cells in the cerebellum, while calcium-permeable glutamate receptors and transporters regulate synaptic circuit development in the somatosensory cortex. Moreover, the GluD2-Cbln1-neurexin system controls the connectivity of parallel fiber-Purkinje cell synapses to compete with climbing fiber innervation promoted by P/Q-type calcium channels.

新生儿突触回路的特点是布线过多、重叠和缠结。通过使用依赖和活动依赖的未成熟突触的加强和削弱/消除，这些不成熟的电路被细化为功能性和成熟的电路。通过这个过程，几乎所有高级大脑功能在出生后早期的敏感或关键时期都得到了蓬勃发展，包括人类的认知、语言、音乐表演、运动、智力、思维、个性和社交性。现在我们了解到，谷氨酸受体激活和随后的钙流入突触后神经元促进了活动依赖性突触回路的发育。然而，人们对钙流入如何调节竞争性突触发育知之甚少。在这个研究项目中，我们旨在利用神经解剖学、电生理学和发育生物技术重点研究钙依赖性和非钙依赖性机制来阐明这个问题。通过这个研究项目，我阐明了P/Q型钙通道促进小脑浦肯野细胞攀爬纤维神经支配的发育和成熟，而钙渗透性谷氨酸受体和转运蛋白则调节体感皮层突触回路的发育。此外，GluD2-Cbln1-neurexin 系统控制平行纤维浦肯野细胞突触的连接，以与 P/Q 型钙通道促进的攀爬纤维神经支配竞争。