Pervasive compartment-specific regulation of gene expression during homeostatic synaptic scaling.
Pervasive compartment-specific regulation of gene expression during homeostatic synaptic scaling.
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DOI：
10.15252/embr.202052094
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发表时间：
2021-10-05
期刊：
影响因子：
7.7
通讯作者：
Schratt G
中科院分区：
文献类型：
--
作者：
Colameo D;Rajman M;Soutschek M;Bicker S;von Ziegler L;Bohacek J;Winterer J;Germain PL;Dieterich C;Schratt G
突触缩放是稳态可塑性的一种形式，其允许神经元响应于神经活动的慢性改变来调整其动作电位放电速率。突触缩放需要基因表达的深刻变化，但局部和细胞范围内机制的相对贡献是有争议的。在这里，我们进行了一个全面的多组学表征的躯体和过程室的原代大鼠海马神经元在突触缩放。我们发现了神经元转录组和蛋白质组的高度区室特异性和相关变化。而神经元兴奋性的关键调节器的下调主要发生在体细胞室，兴奋性突触后的结构成分大多是下调的过程。局部抑制蛋白质合成的过程中缩放确认候选突触蛋白。基序分析进一步表明，反式作用转录后调节因子（包括RNA结合蛋白和microRNA）在相应mRNA的局部调节中发挥重要作用。总之，我们的研究表明，在突触缩放过程中，区室化的基因表达变化可能与神经元范围的机制共存，以实现突触计算和稳态。兴奋性突触对高活性的响应缩小涉及神经元转录组和蛋白质组的隔室特异性变化。这项研究支持了这样的观点，即局部基因调控是重要的，在赫布和稳态形式的突触可塑性。
Synaptic scaling is a form of homeostatic plasticity which allows neurons to adjust their action potential firing rate in response to chronic alterations in neural activity. Synaptic scaling requires profound changes in gene expression, but the relative contribution of local and cell‐wide mechanisms is controversial. Here we perform a comprehensive multi‐omics characterization of the somatic and process compartments of primary rat hippocampal neurons during synaptic scaling. We uncover both highly compartment‐specific and correlating changes in the neuronal transcriptome and proteome. Whereas downregulation of crucial regulators of neuronal excitability occurs primarily in the somatic compartment, structural components of excitatory postsynapses are mostly downregulated in processes. Local inhibition of protein synthesis in processes during scaling is confirmed for candidate synaptic proteins. Motif analysis further suggests an important role for trans‐acting post‐transcriptional regulators, including RNA‐binding proteins and microRNAs, in the local regulation of the corresponding mRNAs. Altogether, our study indicates that, during synaptic scaling, compartmentalized gene expression changes might co‐exist with neuron‐wide mechanisms to allow synaptic computation and homeostasis. Downscaling of excitatory synapses in response to high activity involves compartment‐specific changes in the neuron's transcriptome and proteome. This study supports the view that local gene regulation is important in both Hebbian and homeostatic forms of synaptic plasticity.