PDF(Pubmed)
Abstract：
Circular RNAs (circRNAs) are noncoding RNAs abundant in brain tissue, and many are derived from activity-dependent, linear mRNAs encoding for synaptic proteins, suggesting that circRNAs may directly or indirectly play a role in regulating synaptic development, plasticity, and function. However, it is unclear if the circular forms of these RNAs are similarly regulated by activity and what role these circRNAs play in developmental plasticity. Here, we employed transcriptome-wide analysis comparing differential expression of both mRNAs and circRNAs in juvenile mouse primary visual cortex (V1) following monocular deprivation (MD), a model of developmental plasticity. Among the differentially expressed mRNAs and circRNAs following 3-day MD, the circular and the activity-dependent linear forms of the Homer1 gene, circHomer1 and Homer1a respectively, were of interest as their expression changed in opposite directions: circHomer1 expression increased while the expression of Homer1a decreased following MD. Knockdown of circHomer1 prevented the depression of closed-eye responses normally observed after 3-day MD. circHomer1-knockdown led to a reduction in average dendritic spine size prior to MD, but critically there was no further reduction after 3-day MD, consistent with impaired structural plasticity. circHomer1-knockdown also prevented the reduction of surface AMPA receptors after 3-day MD. Synapse-localized puncta of the AMPA receptor endocytic protein Arc increased in volume after MD but were smaller in circHomer1-knockdown neurons, suggesting that circHomer1 regulates plasticity through mechanisms of activity-dependent AMPA receptor endocytosis. Thus, activity-dependent circRNAs regulate developmental synaptic plasticity, and our findings highlight the essential role of circHomer1 in V1 plasticity induced by short-term MD.
摘要：
环状RNA（circularRNAs，circRNAs）是脑组织中丰富的非编码RNA，许多来自活动依赖，编码突触蛋白的线性mRNA，表明circRNAs可能直接或间接在调节突触发育中发挥作用，可塑性,和功能。然而,尚不清楚这些RNA的环状形式是否受到活性的类似调节，以及这些circRNAs在发育可塑性中起什么作用。这里,我们采用全转录组分析比较mRNAs和circRNAs在幼年小鼠初级视觉皮层（V1）单眼剥夺（MD）后的差异表达，发育可塑性的模型。在3天MD后差异表达的mRNA和circRNAs中，Homer1基因的环状和活性依赖性线性形式，分别为circHomer1和Homer1a，感兴趣的是它们的表达在相反的方向上变化：MD后，circHomer1表达增加，而Homer1a的表达减少。circHomer1的击倒可防止MD3天后通常观察到的闭眼反应的抑制。cirhomer1-knockdown导致MD前平均树突棘大小减少，但关键的是，在3天的MD之后没有进一步的减少，与受损的结构可塑性一致。cirhomer1-敲低也阻止了3天MD后表面AMPA受体的减少。在MD后，AMPA受体内吞蛋白Arc的突触定位点的体积增加，但在circHomer1敲低神经元中更小，提示circHomer1通过活性依赖性AMPA受体内吞作用机制调节可塑性。因此，活性依赖性circRNAs调节发育突触可塑性，我们的发现强调了circHomer1在短期MD诱导的V1可塑性中的重要作用。
■环状RNA(circRNAs)是一类通过外显子和/或内含子连接的反向剪接形成的闭环RNA。最初被认为是功能有限的异常RNA剪接的副产物，最近的研究表明circRNAs与各种神经系统疾病有关。尽管它们在大脑中有丰富的表达，circRNAs在突触功能和可塑性中的作用仍然知之甚少。我们对circRNAs进行了体内转录组分析，这些circRNAs的表达受到视觉皮层中经验依赖性可塑性的调节，发现circHomer1,来自Homer1基因的circRNA，对体内功能可塑性至关重要。发育调节的circomer1通过Arc介导的AMPA受体的内吞作用介导突触可塑性。我们的发现证明了经验依赖性可塑性过程中的circRNA调控，并揭示了它们的功能意义和机制。
■环状RNA(circRNAs)是一类通过外显子和/或内含子连接的反向剪接形成的闭环RNA。最初被认为是功能有限的异常RNA剪接的副产物，最近的研究表明circRNAs与各种神经系统疾病有关。尽管它们在大脑中有丰富的表达，circRNAs在突触功能和可塑性中的作用仍然知之甚少。我们对circRNAs进行了体内转录组分析，这些circRNAs的表达受到视觉皮层中经验依赖性可塑性的调节，发现circHomer1,来自Homer1基因的circRNA，对体内功能可塑性至关重要。发育调节的circomer1通过Arc介导的AMPA受体的内吞作用介导突触可塑性。我们的发现证明了经验依赖性可塑性过程中的circRNA调控，并揭示了它们的功能意义和机制。
