Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; School of Life Science and Technology, Southeast University, 2 Sipailou Road, Nanjing 210096, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Zhongshan Institute for Drug Discovery, the Institutes of Drug Discovery and Development, Chinese Academy of Sciences, Zhongshan, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China.
Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; School of Life Science and Technology, Southeast University, 2 Sipailou Road, Nanjing 210096, China.
Cell Rep. 2021 Aug 17;36(7):109515. doi: 10.1016/j.celrep.2021.109515.
Synaptic scaling is an extensively studied form of homeostatic plasticity critically involved in various brain functions. Although it is accepted that synaptic scaling is expressed through the postsynaptic accumulation of AMPA receptors (AMPARs), the induction mechanism remains elusive. In this study, we show that TTX treatment induces rapid but transient release of the neurite growth-promoting factor 2 (NGPF2), and this release is necessary and sufficient for TTX-induced scaling up. In addition, we show that inhibition of the anaplastic lymphoma kinase (ALK)-LIMK-cofilin signaling pathway blocks TTX- and NGPF2-induced synaptic scaling up. Furthermore, we show that TTX-induced release of NGPF2 is protein synthesis dependent and requires fragile X mental retardation protein 1 (FMRP1). These results indicate that activity blockade induces NGPF2 synthesis and release to trigger synaptic scaling up through LIMK-cofilin-dependent actin reorganization, spine enlargement, and stabilization of AMPARs at the synapse.
突触缩放是一种广泛研究的内稳态可塑性形式，它在各种大脑功能中起着至关重要的作用。尽管人们普遍认为突触缩放是通过 AMPA 受体（AMPAR）的突触后积累来表达的，但诱导机制仍然难以捉摸。在这项研究中，我们表明 TTX 处理会诱导神经营养因子 2（NGPF2）的快速但短暂释放，这种释放对于 TTX 诱导的缩放是必要且充分的。此外，我们表明，抑制间变性淋巴瘤激酶（ALK）-LIMK-丝切蛋白信号通路可阻断 TTX 和 NGPF2 诱导的突触缩放。此外，我们表明，TTX 诱导的 NGPF2 释放依赖于蛋白质合成，并且需要脆性 X 智力低下蛋白 1（FMRP1）。这些结果表明，活性阻断会诱导 NGPF2 的合成和释放，通过 LIMK-丝切蛋白依赖性肌动蛋白重排、棘突增大以及 AMPAR 在突触处的稳定，触发突触缩放。
