Pervasive compartment-specific regulation of gene expression during homeostatic synaptic scaling

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.

突触缩放（synaptic scaling）是稳态可塑性（homeostatic plasticity）的一类形式，可使神经元响应神经活动的慢性改变，调整其动作电位的发放频率。突触缩放需要基因表达发生显著变化，但局部机制与细胞整体机制的相对贡献目前仍存在争议。本研究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。我们揭示了神经元转录组与蛋白质组中兼具高度区室特异性与相关性的变化特征：相较之下，神经元兴奋性关键调控因子的下调主要发生在胞体区室，而兴奋性突触后结构的组分则主要在突起区室中出现下调。针对候选突触蛋白，我们证实了突触缩放过程中突起区室的蛋白质合成存在局部抑制。基序分析（motif analysis）进一步显示，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，在对应信使RNA（mRNAs）的局部调控中发挥重要作用。综上，本研究表明，在突触缩放过程中，区室化的基因表达变化或可与神经元整体机制共存，以实现突触计算与稳态维持。