The brain is known to express many long noncoding RNAs (lncRNAs); however, whether and how these lncRNAs function in modulating synaptic stability remains unclear. Here, we report a cerebellum highly expressed lncRNA, Synage, regulating synaptic stability via at least two mechanisms. One is through the function of Synage as a sponge for the microRNA miR-325-3p, to regulate expression of the known cerebellar synapse organizer Cbln1. The other function is to serve as a scaffold for organizing the assembly of the LRP1-HSP90AA1-PSD-95 complex in PF-PC synapses. Although somewhat divergent in its mature mRNA sequence, the locus encoding Synage is positioned adjacent to the Cbln1 loci in mouse, rhesus macaque, and human, and Synage is highly expressed in the cerebella of all three species. Synage deletion causes a full-spectrum cerebellar ablation phenotype that proceeds from cerebellar atrophy, through neuron loss, on to synapse density reduction, synaptic vesicle loss, and finally to a reduction in synaptic activity during cerebellar development; these deficits are accompanied by motor dysfunction in adult mice, which can be rescued by AAV-mediated Synage overexpression from birth. Thus, our study demonstrates roles for the lncRNA Synage in regulating synaptic stability and function during cerebellar development.

众所周知，大脑会表达许多长链非编码 RNA (lncRNA)；然而，这些 lncRNA 是否以及如何在调节突触稳定性方面发挥作用仍不清楚。在这里，我们报告了一种小脑高表达的 lncRNA，Synage，它通过至少两种机制调节突触稳定性。一种是通过Synage作为 microRNA miR-325-3p 海绵的功能，来调节已知的小脑突触组织者Cbln1的表达。另一个功能是充当支架，用于组织 PF-PC 突触中 LRP1-HSP90AA1-PSD-95 复合体的组装。尽管其成熟 mRNA 序列有些不同，但编码Synage的位点位于Cbln1 附近小鼠、恒河猴和人类中的基因座，而Synage在所有三个物种的小脑中都高度表达。突触缺失导致全谱小脑消融表型，从小脑萎缩开始，通过神经元丢失，再到突触密度降低，突触小泡丢失，最后导致小脑发育过程中突触活动减少；这些缺陷伴随着成年小鼠的运动功能障碍，这可以通过出生时 AAV 介导的Synage过度表达来挽救。因此，我们的研究证明了 lncRNA Synage在小脑发育过程中调节突触稳定性和功能的作用。