加州大学Anna V. Molofsky小组的最新研究揭示了细胞外基质蛋白水解维持大脑发育过程中的突触可塑性。这一研究成果于2025年12月22日发表在国际顶尖学术期刊《自然—神经科学》上。

通过对斑马鱼后脑兴奋性突触的实时成像，该课题组人员观察到短寿命（动态）突触和长寿命（稳定）突触呈双峰分布。通过消化或敲除短蛋白聚糖(brevican)破坏ECM会破坏动态突触的稳定性并导致突触密度降低。相反，基质金属蛋白酶14 （MMP14）的缺失导致短蛋白聚糖的积累，在不影响稳定突触池的情况下，增加了动态突触池的寿命，导致整体突触密度增加。在鱼和人诱导多能干细胞衍生的培养中，小胶质细胞MMP14对这些效应都是必不可少的。在运动学习实验中，MMP14和短蛋白聚糖都是经验依赖的突触可塑性所必需的。这些数据，辅以数学模型，定义了脑外膜重塑在维持大脑发育过程中突触动态子集中的重要作用。

据介绍，细胞外基质（ECM）调节突触可塑性的机制仍在定义中，并且主要在成年期进行了研究。

附：英文原文

Title: Extracellular matrix proteolysis maintains synapse plasticity during brain development

Author: Nakajo, Haruna, Cao, Ran, Mula, Supriya A., McKetney, Justin, Silva, Nicholas J., Li, Kathy H., Chalkley, Robert J., Randolph, Lisa K., Shah, Muskaan, Rose, Indigo V. L., Kampmann, Martin, Swaney, Danielle L., Kirst, Christoph, Molofsky, Anna V.

Issue&Volume: 2025-12-22

Abstract: The extracellular matrix (ECM) regulates synaptic plasticity via mechanisms that are still being defined and have been studied predominantly in adulthood. Here, using live imaging of excitatory synapses in zebrafish hindbrain, we observed a bimodal distribution of short-lived (dynamic) and longer-lived (stable) synapses. Disruption of ECM via digestion or brevican deletion destabilized dynamic synapses and led to decreased synapse density. Conversely, loss of matrix metalloproteinase 14 (MMP14) led to accumulation of brevican and increased the lifetime of the dynamic synapse pool without affecting the stable synapse pool, resulting in increased overall synapse density. Microglial MMP14 was essential to these effects in both fish and human induced pluripotent stem cell-derived cultures. Both MMP14 and brevican were required for experience-dependent synapse plasticity in a motor learning assay. These data, complemented by mathematical modeling, define an essential role of ECM remodeling in maintaining a dynamic subset of synapses during brain development.

DOI: 10.1038/s41593-025-02153-4

Source: https://www.nature.com/articles/s41593-025-02153-4