Molecular mechanisms for competitive synaptic wiring in cerebellar Purlfinje cells

小脑浦肯野细胞（Purkinje cells，PC）的平行纤维（parallel fibers，PFs）和攀缘纤维（climbing fibers，CFs）神经支配是研究突触回路发育和成熟的最佳模型系统之一。通过我们先前对PF突触特异性分子GluRd 2的分析，我们已经表明该分子通过PF加强突触发生。在没有GluRd 2的情况下，PF-PCPC突触的数量显著减少，并且远端树突上的许多PC棘变得没有突触接触（Kurihara等人，1997，J.Neurosci.17：9613-9623）。在这个研究项目中，我们的目的是澄清在PF突触发生减弱的情况下，CF在神经支配中发生了什么。通过采用顺行示踪标记和免疫标记，远端延伸CF的神经支配发生在GluRd 2基因敲除小鼠和受神经支配的PC远端树突上的游离棘。远端延伸进一步发生在邻近PC上的远端树突上，导致神经支配中的多个CF（Hahimoto等人，2001;J.Neurosci.21：9701-9712 ; Ichikawa等人，22：8487-8503）。这些结果表明，PC树突上的突触发生是基于PF和CF之间的积极竞争，其中GluRd 2加强了PF对远端树突的神经支配。此外，我们进一步揭示了由CF激活并诱导钙流入PC树突的P/Q型钙通道α-1A是通过近端树突处的单个主要CF加强神经支配并从树突排出其他较小CF和PF的分子机制（宫崎et al.，24：1734-1743）。

Innervation of cerebellar Purkinje cells (PCs) by parallel fibers (PFs) and climbing fibers (CFs) is one of the best model system for synaptic circuit development and maturation. Through our previous analysis on PF synapse-specific molecule GluRd2, we have shown that this molecule strengthens synaptogenesis by PFs. Without GluRd2, PF-PCPC synapses are markedly reduced in number, and many PC spines on distal dendrites became free of synaptic contact (Kurihara et al.,1997, J.Neurosci.17:9613-9623). In this research project, we aimed to clarify what happens for CF in nervation under weakened PF synaptogenesis. By employing anterograde tracer labeling and immunolabeling, distal extension of CF in nervation was shown to occur in GluRd2 knockout mice and innervated free spines on distal dendrites of the PC. The distal extension further occurred against distal dendrites on adjacent PCs, resulting in multiple CF in nervation (Hahimoto et al.,2001;J.Neurosci.21:9701-9712 ; Ichikawa et al.,2002, J.Neurosci.22:8487-8503). These results indicate that synaptogenesis on PC dendrites stands on active competition between PF and CF, in which GluRd2 strengthens PF innervation to distal dendrites. Furthermore, we further revealed that P/Q-type calcium channel alpha-1A, which is activated by CF and induces calcium influx to PC dendrites, is the molecular mechanism that strengthens in nervation by a single major CF at proximal dendrites and expels other lesser CFs and PFs from the dendrites (Miyazaki et al.,2004, J.Neurosci.24:1734-1743).