MicroRNA regulation of homeostatic synaptic plasticity
MicroRNA regulation of homeostatic synaptic plasticity
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DOI：
10.1073/pnas.1017576108
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发表时间：
2011-07-12
影响因子：
11.1
通讯作者：
Fields, R. Douglas
中科院分区：
文献类型：
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作者：
Cohen, Jonathan E.;Lee, Philip R.;Fields, R. Douglas
需要稳态机制来控制突触连接的形成和维持，以将神经冲动活动的一般水平维持在正常范围内。控制这些过程的基因如何在稳态突触可塑性过程中协同调节尚不清楚。 MicroRNA (miRNA) 对 mRNA 稳定性和翻译发挥调节控制作用，并可能有助于突触相关 mRNA 的局部和活性依赖性转录后控制。然而，识别通过突触转录后基因沉默发挥作用的 miRNA 仍然难以实现。使用生物信息学筛选来鉴定快速不稳定的 mRNA 3'UTR 中富集的序列基序，我们鉴定了一种发育和活性调节的 miRNA (miR-485)，它以活性依赖的稳态方式控制树突棘数量和突触形成。我们发现许多可塑性相关基因含有预测的 miR-485 结合位点，并进一步确定突触前蛋白 SV2A 作为 miR-485 的靶点。 miR-485 负向调节树突棘密度、突触后密度 95 (PSD-95) 聚类和 GluR2 的表面表达。此外，通过微型兴奋性突触后电流 (EPSC) 分析和 FM 1-43 染色测量，miR-485 过表达减少了自发突触反应和递质释放。 SV2A 敲低模仿了 miR-485 的作用，而这些作用可通过 SV2A 过表达而逆转。此外，突触活性增加 5 天会诱导突触特化发生稳态变化，而这种变化可被 miR-485 抑制剂阻断。我们的研究结果揭示了这种先前未表征的 miRNA 和突触前蛋白 SV2A 在稳态可塑性和神经系统发育中的作用，可能对神经系统疾病（例如亨廷顿病和阿尔茨海默氏病）有影响，其中 miR-485 被发现失调。
Homeostatic mechanisms are required to control formation and maintenance of synaptic connections to maintain the general level of neural impulse activity within normal limits. How genes controlling these processes are co-coordinately regulated during homeostatic synaptic plasticity is unknown. MicroRNAs (miRNAs) exert regulatory control over mRNA stability and translation and may contribute to local and activity-dependent posttranscriptional control of synapse-associated mRNAs. However, identifying miRNAs that function through posttranscriptional gene silencing at synapses has remained elusive. Using a bioinformatics screen to identify sequence motifs enriched in the 3'UTR of rapidly destabilized mRNAs, we identified a developmentally and activity-regulated miRNA (miR-485) that controls dendritic spine number and synapse formation in an activity-dependent homeostatic manner. We find that many plasticity-associated genes contain predicted miR-485 binding sites and further identify the presynaptic protein SV2A as a target of miR-485. miR-485 negatively regulated dendritic spine density, postsynaptic density 95 (PSD-95) clustering, and surface expression of GluR2. Furthermore, miR-485 overexpression reduced spontaneous synaptic responses and transmitter release, as measured by miniature excitatory postsynaptic current (EPSC) analysis and FM 1-43 staining. SV2A knockdown mimicked the effects of miR-485, and these effects were reversed by SV2A overexpression. Moreover, 5 d of increased synaptic activity induced homeostatic changes in synaptic specializations that were blocked by a miR-485 inhibitor. Our findings reveal a role for this previously uncharacterized miRNA and the presynaptic protein SV2A in homeostatic plasticity and nervous system development, with possible implications in neurological disorders (e. g., Huntington and Alzheimer's disease), where miR-485 has been found to be dysregulated.