REST-Dependent Presynaptic Homeostasis Induced by Chronic Neuronal Hyperactivity
REST-Dependent Presynaptic Homeostasis Induced by Chronic Neuronal Hyperactivity
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DOI：
10.1007/s12035-017-0698-9
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发表时间：
2018-06-01
影响因子：
5.1
通讯作者：
Baldelli, Pietro
中科院分区：
文献类型：
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作者：
Pecoraro-Bisogni, F.;Lignani, Gabriele;Baldelli, Pietro
稳态可塑性是一种调节反馈反应，其中突触强度或内在兴奋性可以向上或向下调整，以抵消神经元活动的持续变化。尽管越来越多的证据不断为这两个明显不同的稳态过程提供新的见解，但统一的分子模型仍然未知。我们最近证明，REST 是一种转录抑制因子，对于降低长期电活动升高的培养海马神经元的内在兴奋性至关重要。在这里，我们报告说，在同一实验系统中，REST 还通过专门作用于突触前水平来降低兴奋性突触的强度，从而参与突触稳态。事实上，慢性过度活跃通过特定突触前 REST 靶基因的转录和翻译抑制，引发 REST 依赖性突触小泡池大小的减小。与我们之前的报告一起，这些数据将 REST 确定为神经元稳态的基本分子参与者，能够同时降低内在兴奋性和突触前效率，以响应神经元活动的升高。这一实验证据为 REST 介导的稳态可塑性过程的复杂的活动依赖性转录调节提供了新的见解。
Homeostatic plasticity is a regulatory feedback response in which either synaptic strength or intrinsic excitability can be adjusted up or down to offset sustained changes in neuronal activity. Although a growing number of evidences constantly provide new insights into these two apparently distinct homeostatic processes, a unified molecular model remains unknown. We recently demonstrated that REST is a transcriptional repressor critical for the downscaling of intrinsic excitability in cultured hippocampal neurons subjected to prolonged elevation of electrical activity. Here, we report that, in the same experimental system, REST also participates in synaptic homeostasis by reducing the strength of excitatory synapses by specifically acting at the presynaptic level. Indeed, chronic hyperactivity triggers a REST-dependent decrease of the size of synaptic vesicle pools through the transcriptional and translational repression of specific presynaptic REST target genes. Together with our previous report, the data identify REST as a fundamental molecular player for neuronal homeostasis able to downscale simultaneously both intrinsic excitability and presynaptic efficiency in response to elevated neuronal activity. This experimental evidence adds new insights to the complex activity-dependent transcriptional regulation of the homeostatic plasticity processes mediated by REST.