Calcium Signaling and Cerebellar Synaptic Circuit Development

突触的形成在很大程度上取决于多个输入源对单个神经元的竞争。小脑浦肯野细胞具有高度组织化的突触连接，来自两个不同的兴奋性传入源。单个攀爬纤维支配浦肯野细胞的近端树突，而许多平行纤维聚集在浦肯野细胞的远端树突上。在这里，我们证明了P/ q型Ca^<2+>通道a1A是浦肯野细胞中主要的Ca^<2+>通道亚型，对这种有组织的突触形成至关重要。在alA基因敲除小鼠中，浦肯野细胞近端树突和体细胞中经常观察到异位棘形成。平行纤维的神经支配范围向近端扩展，支配这些异位棘，而攀爬纤维的神经支配范围则向近端树突和躯体的基底部退行。此外，在大多数浦肯野细胞中存在由一个强攀爬纤维和一个或几个弱攀爬纤维组成的多个攀爬纤维，并与基底体突结构域共连接。因此，alA的缺乏导致平行纤维和多余的攀爬纤维存活，这些纤维通常应该从主攀爬纤维支配的隔室中排出。我们得出结论，P/ q型Ca^<2+>通道alA既促进了攀爬纤维与平行纤维之间的异突触竞争，也促进了多个攀爬纤维之间的同突触竞争。这一分子功能促进了攀爬纤维神经支配沿浦肯野细胞树突树的远端延伸，也建立了单个浦肯野细胞的单一攀爬纤维神经支配。

Synapse formation depends critically on the competition among inputs of multiple sources to individual neurons. Cerebellar Purkinje cells have highly organized synaptic wiring from two distinct sources of excitatory afferents. Single climbing fibers innervate proximal dendrites of Purkinje cells, whereas numerous parallel fibers converge on their distal dendrites. Here, we demonstrate that the P/Q-type Ca^<2+> channel a1A, a major Ca^<2+> channel subtype in Purkinje cells, is crucial for this organized synapse formation. In the alA knockout mouse, ectopic spine formation was frequently observed in proximal dendrites and somata of Purkinje cells. Innervation territory of parallel fibers was expanded proximally to innervate these ectopic spines, whereas that of climbing fibers was regressed to the basal portion of proximal dendrites and somata. Furthermore, multiple climbing fibers, consisting of a strong climbing fiber and one or a few weaker ones, persisted in the majority of Purkinje cells and were co-wired to the basal somatodendritic domain. The lack of alA, therefore, results in the survival of parallel fibers and surplus climbing fibers, which should normally be expelled from the compartment innervated by the main climbing fiber. We conclude that a P/Q-type Ca^<2+> channel alA fuels both heterosynaptic competition between climbing fibers and parallel fibers and homosynaptic competition among multiple climbing fibers. This molecular function facilitates the distal extension of climbing fiber innervation along Purkinje cell's dendritic tree and also establishes mono climbing fiber innervation of individual Purkinje cells.