Zhong Ling, Gerges Nashaat Z
Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI, United States.
Front Mol Neurosci. 2020 Jan 24;12:322. doi: 10.3389/fnmol.2019.00322. eCollection 2019.
Long-term potentiation (LTP) and long-term depression (LTD) are two major forms of synaptic plasticity that are widely accepted as cellular mechanisms involved in learning and memory. Metaplasticity is a process whereby modifications in synaptic processes shift the threshold for subsequent plasticity. While metaplasticity has been functionally observed, its molecular basis is not well understood. Here, we report that neurogranin (Ng) regulates metaplasticity by shifting the threshold toward potentiation, i.e., increasing Ng in hippocampal neurons lowers the threshold for LTP and augments the threshold for LTD. We also show that Ng does not change the ultrastructural localization of calmodulin (CaM)-dependent protein Kinase II (CaMKII) or calcineurin, critical enzymes for the induction of LTP and LTD, respectively. Interestingly, while CaMKII concentrates close to the plasma membrane, calcineurin concentrates away from the plasma membrane. These data, along with the previous observation showing Ng targets CaM closer to the plasma membrane, suggesting that shifting the localization of CaM within the dendritic spines and closer to the plasma membrane, where there is more CaMKII, may be favoring the activation of CaMKII vs. that of calcineurin. Thus, the regulation of CaM localization/targeting within dendritic spines by Ng may provide a mechanistic basis for the regulation of metaplasticity.
长时程增强（LTP）和长时程抑制（LTD）是突触可塑性的两种主要形式，被广泛认为是参与学习和记忆的细胞机制。元可塑性是一种突触过程的修饰会改变后续可塑性阈值的过程。虽然元可塑性已在功能上得到观察，但其分子基础仍未得到很好的理解。在此，我们报告神经颗粒素（Ng）通过将阈值向增强方向移动来调节元可塑性，即增加海马神经元中的Ng会降低LTP的阈值并提高LTD的阈值。我们还表明，Ng不会改变钙调蛋白（CaM）依赖性蛋白激酶II（CaMKII）或钙调神经磷酸酶的超微结构定位，这两种酶分别是诱导LTP和LTD的关键酶。有趣的是，虽然CaMKII集中在靠近质膜的位置，但钙调神经磷酸酶集中在远离质膜的位置。这些数据，连同先前观察到的Ng将CaM靶向更靠近质膜的结果，表明在树突棘内将CaM的定位向更靠近质膜的位置移动，那里有更多的CaMKII，可能有利于CaMKII而非钙调神经磷酸酶的激活。因此，Ng对树突棘内CaM定位/靶向的调节可能为元可塑性的调节提供一个机制基础。
