Compartment-specific regulation of gene expression orchestrates homeostatic synaptic scaling

Synaptic scaling is a form of homeostatic plasticity which allows neurons to reduce 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 to synaptic scaling is controversial. Here we performed a comprehensive multi-omics characterization of the somatic and process compartments of primary rat hippocampal neurons during synaptic scaling. Thereby, we uncovered highly compartment-specific and correlated changes in the neuronal transcriptome and proteome. Specifically, we identified highly compartment-specific downregulation of crucial regulators of neuronal excitability and excitatory synapse structure. 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 compartmentalized gene expression changes are widespread in synaptic scaling and might co-exist with neuron-wide mechanism to allow synaptic computation and homeostasis.突触缩放（Synaptic scaling）是一类稳态可塑性（homeostatic plasticity）形式，可使神经元响应神经活动的慢性改变，降低自身的动作电位发放频率。突触缩放需要基因表达发生显著改变，但局部与全细胞机制对突触缩放的相对贡献仍存在争议。本研究针对突触缩放过程中原代大鼠海马神经元的胞体与突起区室开展了全面的多组学（multi-omics）表征。借此，我们揭示了神经元转录组（transcriptome）与蛋白质组（proteome）中高度区室特异性且具有相关性的变化。具体而言，我们鉴定出神经元兴奋性与兴奋性突触结构关键调控因子的区室特异性下调现象。基序分析（Motif analysis）进一步表明，包括RNA结合蛋白（RNA-binding proteins）与微小RNA（microRNAs）在内的反式作用转录后调控因子，在对应mRNA的局部调控中发挥重要作用。综上，本研究表明区室化基因表达变化在突触缩放过程中广泛存在，或可与全神经元机制共存，以实现突触计算与稳态维持。