Division of Biological Sciences, and Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, California, United States of America.
PLoS One. 2014 Apr 16;9(4):e94787. doi: 10.1371/journal.pone.0094787. eCollection 2014.
A current model posits that cofilin-dependent actin severing negatively impacts dendritic spine volume. Studies suggested that increased cofilin activity underlies activity-dependent spine shrinkage, and that reduced cofilin activity induces activity-dependent spine growth. We suggest instead that both types of structural plasticity correlate with decreased cofilin activity. However, the mechanism of inhibition determines the outcome for spine morphology. RNAi in rat hippocampal cultures demonstrates that cofilin is essential for normal spine maintenance. Cofilin-F-actin binding and filament barbed-end production decrease during the early phase of activity-dependent spine shrinkage; cofilin concentration also decreases. Inhibition of the cathepsin B/L family of proteases prevents both cofilin loss and spine shrinkage. Conversely, during activity-dependent spine growth, LIM kinase stimulates cofilin phosphorylation, which activates phospholipase D-1 to promote actin polymerization. These results implicate novel molecular mechanisms and prompt a revision of the current model for how cofilin functions in activity-dependent structural plasticity.
当前的模型假设肌动蛋白解聚酶依赖的胞质分裂蛋白依赖性肌动蛋白的切割会对树突棘体积产生负面影响。研究表明，细胞活跃时，肌动蛋白解聚酶活性增加，会导致树突棘缩小，而肌动蛋白解聚酶活性降低则会诱导树突棘生长。但我们认为，这两种类型的结构可塑性都与肌动蛋白解聚酶活性降低有关。然而，抑制的机制决定了脊柱形态的结果。在大鼠海马培养物中的 RNAi 表明，肌动蛋白解聚酶对于维持正常的脊柱至关重要。在细胞活跃时导致树突棘缩小的早期阶段，肌动蛋白解聚酶与 F-肌动蛋白的结合以及丝状的突出端的产生减少；肌动蛋白解聚酶的浓度也降低。抑制组织蛋白酶 B/L 蛋白酶家族可以防止肌动蛋白解聚酶的丢失和树突棘的缩小。相反，在细胞活跃时导致树突棘生长的过程中，LIM 激酶刺激肌动蛋白解聚酶的磷酸化，从而激活磷酯酶 D-1 来促进肌动蛋白聚合。这些结果表明存在新的分子机制，并促使对肌动蛋白解聚酶在细胞活跃的结构可塑性中作用的当前模型进行修订。
