The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
Department of Basic Sciences, Universitat Internacional de Catalunya, 08195, Sant Cugat del Vallès, Spain.
Mol Psychiatry. 2021 Sep;26(9):4652-4669. doi: 10.1038/s41380-020-0821-6. Epub 2020 Jul 1.
Many neurodevelopmental disorders are characterized by impaired functional synaptic plasticity and abnormal dendritic spine morphology, but little is known about how these are related. Previous work in the Fmr1 mouse model of fragile X (FX) suggests that increased constitutive dendritic protein synthesis yields exaggerated mGluR5-dependent long-term synaptic depression (LTD) in area CA1 of the hippocampus, but an effect on spine structural plasticity remains to be determined. In the current study, we used simultaneous electrophysiology and time-lapse two photon imaging to examine how spines change their structure during LTD induced by activation of mGluRs or NMDA receptors (NMDARs), and how this plasticity is altered in Fmr1 mice. We were surprised to find that mGluR activation causes LTD and AMPA receptor internalization, but no spine shrinkage in either wildtype or Fmr1 mice. In contrast, NMDAR activation caused spine shrinkage as well as LTD in both genotypes. Spine shrinkage was initiated by non-ionotropic (metabotropic) signaling through NMDARs, and in wild-type mice this structural plasticity required activation of mTORC1 and new protein synthesis. In striking contrast, NMDA-induced spine plasticity in Fmr1 mice was no longer dependent on acute activation of mTORC1 or de novo protein synthesis. These findings reveal that the structural consequences of mGluR and metabotropic NMDAR activation differ, and that a brake on spine structural plasticity, normally provided by mTORC1 regulation of protein synthesis, is absent in FX. Increased constitutive protein synthesis in FX appears to modify functional and structural plasticity induced through different glutamate receptors.
许多神经发育障碍的特征是功能突触可塑性受损和树突棘形态异常，但人们对它们之间的关系知之甚少。脆性 X 综合征（FX）的 Fmr1 小鼠模型的先前研究表明，组成型树突蛋白合成增加会导致海马 CA1 区的 mGluR5 依赖性长时程突触抑制（LTD）过度，但其对树突棘结构可塑性的影响仍有待确定。在当前的研究中，我们使用同时进行的电生理学和延时双光子成像来研究 mGluRs 或 NMDA 受体（NMDARs）激活时，树突棘如何改变其结构，以及这种可塑性在 Fmr1 小鼠中如何改变。我们惊讶地发现，mGluR 激活会导致 LTD 和 AMPA 受体内化，但在野生型或 Fmr1 小鼠中均不会导致树突棘收缩。相比之下，NMDAR 激活会导致两种基因型的树突棘收缩和 LTD。树突棘收缩是由 NMDAR 的非离子型（代谢型）信号触发的，在野生型小鼠中，这种结构可塑性需要 mTORC1 的激活和新的蛋白质合成。相比之下，在 Fmr1 小鼠中，NMDAR 诱导的树突棘可塑性不再依赖于 mTORC1 的急性激活或新的蛋白质合成。这些发现表明，mGluR 和代谢型 NMDAR 激活的结构后果不同，并且通常由 mTORC1 调节蛋白质合成提供的树突棘结构可塑性的刹车在 FX 中缺失。FX 中组成型蛋白质合成的增加似乎改变了通过不同谷氨酸受体诱导的功能和结构可塑性。
