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

新生儿的突触回路的特点是多余的，重叠和纠缠的布线。这些未成熟的回路通过使用依赖性和活动依赖性的加强和弱化/消除未成熟的突触而被细化为功能性和成熟的回路。通过这个过程，几乎所有的高级大脑功能在出生后早期的敏感或关键时期都得到了有力的发展，包括人类的认知，语言，音乐表演，运动，智力，思想，个性和社会性。现在我们知道，活动依赖性突触回路的发展是由谷氨酸受体激活和随后的钙离子流入突触后神经元促进的。然而，很少有人知道钙离子内流如何调节竞争性突触发育。在这个研究项目中，我们的目的是澄清这个问题，重点是钙依赖性和非依赖性机制，使用神经解剖学，电生理学和发育生物学技术。通过这个研究项目，我澄清了P/Q型钙通道促进小脑浦肯野细胞的攀爬纤维神经支配的发展和成熟，而钙渗透性谷氨酸受体和转运蛋白调节体感皮层突触回路的发展。此外，GluD 2-Cbln 1-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。

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.