Division of Cellular Neurobiology, Zoological Institute, TU Braunschweig, Germany.
Helmholtz Center for Infection Research, Research group Neuroinflammation and Neurodegeneration, Braunschweig, Germany.
Cereb Cortex. 2019 Dec 17;29(12):5204-5216. doi: 10.1093/cercor/bhz059.
Multiple variants of intellectual disability, e.g., the Fragile X Syndrome are associated with alterations in dendritic spine morphology, thereby pointing to dysregulated actin dynamics during development and processes of synaptic plasticity. Surprisingly, although the necessity of spine actin remodeling was demonstrated repeatedly, the importance and precise role of actin regulators is often undervalued. Here, we provide evidence that structural and functional plasticity are severely impaired after NMDAR-dependent LTP in the hippocampus of Fmr1 KO mice. We can link these defects to an aberrant activity-dependent regulation of Cofilin 1 (cof1) as activity-dependent modulations of local cof1 mRNA availability, local cof1 translation as well as total cof1 expression are impaired in the absence of FMRP. Finally, we can rescue activity-dependent structural plasticity in KO neurons by mimicking the regulation of cof1 observed in WT cells, thereby illustrating the potential of actin modulators to provide novel treatment strategies for the Fragile X Syndrome.
多种智力障碍的变体，例如脆性 X 综合征，与树突棘形态的改变有关，从而表明在发育过程中和突触可塑性的过程中肌动蛋白动力学失调。令人惊讶的是，尽管已经反复证明了棘突肌动蛋白重塑的必要性，但肌动蛋白调节剂的重要性和确切作用常常被低估。在这里，我们提供的证据表明，在 Fmr1 KO 小鼠的海马体中，NMDAR 依赖性 LTP 后结构和功能的可塑性严重受损。我们可以将这些缺陷与 Cofilin 1（cof1）的异常活性依赖性调节联系起来，因为在没有 FMRP 的情况下，局部 cof1 mRNA 可用性、局部 cof1 翻译以及总 cof1 表达的活性依赖性调节都会受到损害。最后，我们可以通过模拟 WT 细胞中观察到的 cof1 调节来挽救 KO 神经元中的活性依赖性结构可塑性，从而说明了肌动蛋白调节剂为脆性 X 综合征提供新的治疗策略的潜力。
