An intrinsic transcriptional program underlying synaptic scaling during activity suppression

Homeostatic scaling allows neurons to maintain stable activity patterns by globally altering their synaptic strength in response to changing activity levels. Suppression of activity by blocking action potentials increases synaptic strength through an upregulation of surface AMPA receptors. Although this synaptic up-scaling was shown to require transcription, the molecular nature of the intrinsic transcription program underlying this process and its functional significance have been unclear. Using RNA-seq, we identified 73 genes that were specifically upregulated in response to activity suppression. In particular, Neuronal pentraxin-1 (Nptx1) increased within 6 h of activity blockade, and knockdown of this gene blocked the increase in synaptic strength. Notably, Nptx1 induction is mediated by calcium influx through the T-type Voltage-Gated Calcium Channel, as well as two transcription factors, SRF and ELK1. Taken together, these results uncover a transcriptional program that specifically operates when neuronal activity is suppressed, to globally coordinate the increase in synaptic strength. mRNA profiles were generated from primary mouse cortical neurons at DIV12, comparing untreated neurons to neurons treated with Bicuculline or TTX for 30 m, 2 h, 4h, or 6 h, in duplicate

突触稳态缩放（Homeostatic scaling）可通过全局调控突触强度以响应活动水平的变化，帮助神经元维持稳定的活动模式。通过阻断动作电位抑制神经元活动，可通过上调表面AMPA受体（AMPA receptor）增强突触强度。尽管已知该突触上调过程依赖转录调控，但支撑这一过程的内在转录程序的分子本质及其功能意义此前仍不明晰。本研究借助RNA测序（RNA-seq）鉴定出73个响应活动抑制发生特异性上调的基因。具体而言，神经元五聚蛋白1（Neuronal pentraxin-1, Nptx1）在活动阻断后6小时内表达上调，且敲低该基因可阻断突触强度的提升。值得注意的是，Nptx1的诱导表达依赖于T型电压门控钙通道（T-type Voltage-Gated Calcium Channel）介导的钙离子内流，以及两种转录因子SRF与ELK1。综上，本研究揭示了一套仅在神经元活动受抑制时激活的转录程序，可全局协同调控突触强度的提升。本研究的mRNA表达谱源自体外培养第12天（DIV12）的原代小鼠皮层神经元，实验设置未经处理的对照组，以及分别用荷包牡丹碱（Bicuculline）或TTX处理30分钟、2小时、4小时或6小时的实验组，所有样本均设置双重复。