Activity-Dependent Repression of Cbln1 Expression: Mechanism for Developmental and Homeostatic Regulation of Synapses in the Cerebellum
Activity-Dependent Repression of Cbln1 Expression: Mechanism for Developmental and Homeostatic Regulation of Synapses in the Cerebellum
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DOI：
10.1523/jneurosci.4473-08.2009
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发表时间：
2009-04-29
影响因子：
5.3
通讯作者：
Yuzaki, Michisuke
中科院分区：
文献类型：
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作者：
Iijima, Takatoshi;Emi, Kyoichi;Yuzaki, Michisuke
Cbln1属于C1q/肿瘤坏死因子超家族，从小脑颗粒细胞中释放，不仅在发育过程中，而且在成年小脑中，在平行纤维（PFs；颗粒细胞轴突）和浦肯野细胞之间的兴奋性突触的形成和维持中起着至关重要的作用。虽然已知神经元活动会引起突触的形态变化，但神经元活动如何影响Cbln1信号仍不清楚。在这里，我们表明，通过提高细胞外K+水平或通过添加kainate来慢性刺激神经元活性，在成熟颗粒细胞中，在几小时内以依赖于l型电压依赖性Ca2+通道和钙调磷酸酶的方式降低了cbln1 mRNA的表达。慢性活动也会在几天内降低Cbln1蛋白水平，在此期间浦肯野细胞树突上的兴奋性突触数量减少；在培养基中加入外源的Cbln1可以防止这种活性诱导的突触减少。因此，cbln1的活性依赖性下调可能是一种新的突触前机制，通过这种机制，pf -浦肯野细胞突触适应长期升高的活性，从而维持体内平衡。此外，在高k +培养基中维持未成熟颗粒细胞可阻止cbln1 mRNA的表达。由于未成熟颗粒细胞在迁移到内颗粒层之前是慢性去极化的，这种依赖于去极化的cbln1 mRNA表达调节也可能作为发育开关，促进内颗粒层成熟颗粒细胞中PF突触的形成。
Cbln1, which belongs to the C1q/tumor necrosis factor superfamily, is released from cerebellar granule cells and plays a crucial role in forming and maintaining excitatory synapses between parallel fibers (PFs; axons of granule cells) and Purkinje cells not only during development but also in the adult cerebellum. Although neuronal activity is known to cause morphological changes at synapses, how Cbln1 signaling is affected by neuronal activity remains unclear. Here, we show that chronic stimulation of neuronal activity by elevating extracellular K+ levels or by adding kainate decreased the expression of cbln1 mRNA within several hours in mature granule cells in a manner dependent on L-type voltage-dependent Ca2+ channels and calcineurin. Chronic activity also reduced Cbln1 protein levels within a few days, during which time the number of excitatory synapses on Purkinje cell dendrites was reduced; this activity-induced reduction of synapses was prevented by the addition of exogenous Cbln1 to the culture medium. Therefore, the activity-dependent downregulation of cbln1 may serve as a new presynaptic mechanism by which PF-Purkinje cell synapses adapt to chronically elevated activity, thereby maintaining homeostasis. In addition, the expression of cbln1 mRNA was prevented when immature granule cells were maintained in high-K+ medium. Since immature granule cells are chronically depolarized before migrating to the internal granule layer, this depolarization-dependent regulation of cbln1 mRNA expression may also serve as a developmental switch to facilitate PF synapse formation in mature granule cells in the internal granule layer.