Activity-Dependent Secretion of Synaptic Organizer Cbln1 from Lysosomes in Granule Cell Axons
Activity-Dependent Secretion of Synaptic Organizer Cbln1 from Lysosomes in Granule Cell Axons
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DOI：
10.1016/j.neuron.2019.03.044
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发表时间：
2019-06-19
期刊：
影响因子：
16.2
通讯作者：
Yuzaki, Michisuke
中科院分区：
文献类型：
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作者：
Ibata, Keiji;Kono, Maya;Yuzaki, Michisuke
突触的形成是由各种突触组织者完成的。虽然这一过程受到神经元活动的高度调节，但其潜在的分子机制仍不清楚。在这里，我们表明，Cbln1，C1q家族的突触组织者，从溶酶体中释放的轴突，但不是树突的小脑颗粒细胞的活性和Ca2+依赖的方式。胞吐的Cbln1通过与突触前受体neurexin结合而保留在轴突表面。CBLN 1进一步沿轴突表面沿着横向扩散，并通过结合突触后δ 2谷氨酸受体在终扣处聚集。Cbln 1的胞吐作用对破伤风神经毒素不敏感，伴随着组织蛋白酶B的释放，并通过破坏溶酶体而减少。此外，溶酶体唾液酸酶Neu1的过表达不仅在体外抑制Cbln 1和组织蛋白酶B的胞吐作用，而且在体内减少轴突终接形成。我们的研究结果表明，共同释放的Cbln 1和组织蛋白酶B从溶酶体作为一个新的机制的活动依赖性协调突触修饰。
Synapse formation is achieved by various synaptic organizers. Although this process is highly regulated by neuronal activity, the underlying molecular mechanisms remain largely unclear. Here we show that Cbln1, a synaptic organizer of the C1q family, is released from lysosomes in axons but not dendrites of cerebellar granule cells in an activity- and Ca2+-dependent manner. Exocytosed Cbln1 was retained on axonal surfaces by binding to its presynaptic receptor neurexin. Cbln1 further diffused laterally along the axonal surface and accumulated at boutons by binding postsynaptic delta 2 glutamate receptors. Cbln1 exocytosis was insensitive to tetanus neurotoxin, accompanied by cathepsin B release, and decreased by disrupting lysosomes. Furthermore, overexpression of lysosomal sialidase Neu1 not only inhibited Cbln1 and cathepsin B exocytosis in vitro but also reduced axonal bouton formation in vivo. Our findings imply that co-release of Cbln1 and cathepsin B from lysosomes serves as a new mechanism of activity-dependent coordinated synapse modification.