ABSTRACT

For network rewiring and information storage in the brain, late phase long-term synaptic depression (L-LTD) requires the long-lasting reorganization of cellular resources. We found that activation of GRIN/NMDAR recruits transcription-dependent autophagy for synaptic turnover to support L-LTD. Activity-dependent CRTC1 synapto-nuclear translocation increases nuclear CRTC1 that competes with FXR for binding to CREB; this in turn enhances the direct binding between CRTC1-CREB and macroautophagy/autophagy gene promoters. Synergistic actions of CRTC1-CREB are preferentially turned on by LTD-inducing stimuli and switched off by genetic knockdown of CREB or CRTC1, or acutely activating FXR. Disrupted CRTC1-CREB signaling impairs activity-driven loss of surface GRIA/AMPARs and DLG4/PSD-95, and selectively prevents GRIN/NMDAR-dependent L-LTD, which are rescued by enhancing MTOR-regulated autophagy. These findings suggest a novel mechanism in L-LTD, in which brief synaptic activities recruit long-lasting autophagy through excitation-transcription coupling for ensuing synaptic remodeling.

摘要

对于大脑中的网络重新布线和信息存储，晚期长期突触抑制 (L-LTD) 需要对细胞资源进行长期重组。我们发现 GRIN/NMDAR 的激活会募集转录依赖性自噬以进行突触转换以支持 L-LTD。活性依赖性 CRTC1 突触核易位增加了与 FXR 竞争结合 CREB ​​的核 CRTC1；这反过来又增强了 CRTC1-CREB ​​和巨自噬/自噬基因启动子之间的直接结合。CRTC1-CREB ​​的协同作用优先通过 LTD 诱导刺激打开，并通过 CREB ​​或 CRTC1 的基因敲低或急性激活 FXR 关闭。中断的 CRTC1-CREB ​​信号会损害表面 GRIA/AMPAR 和 DLG4/PSD-95 的活动驱动损失，并选择性地阻止 GRIN/NMDAR 依赖的 L-LTD，通过增强 MTOR 调节的自噬来挽救。这些发现表明了 L-LTD 中的一种新机制，其中短暂的突触活动通过激发 - 转录耦合募集持久的自噬，以随后进行突触重塑。