Bridi Morgan, Schoch Hannah, Florian Cédrick, Poplawski Shane G, Banerjee Anamika, Hawk Joshua D, Porcari Giulia S, Lejards Camille, Hahn Chang-Gyu, Giese Karl-Peter, Havekes Robbert, Spruston Nelson, Abel Ted
Mahoney Institute for Neurosciences.
Cell and Molecular Biology Graduate Group.
JCI Insight. 2020 Mar 12;5(5):92385. doi: 10.1172/jci.insight.92385.
Long-term memory depends on the control of activity-dependent neuronal gene expression, which is regulated by epigenetic modifications. The epigenetic modification of histones is orchestrated by the opposing activities of 2 classes of regulatory complexes: permissive coactivators and silencing corepressors. Much work has focused on coactivator complexes, but little is known about the corepressor complexes that suppress the expression of plasticity-related genes. Here, we define a critical role for the corepressor SIN3A in memory and synaptic plasticity, showing that postnatal neuronal deletion of Sin3a enhances hippocampal long-term potentiation and long-term contextual fear memory. SIN3A regulates the expression of genes encoding proteins in the postsynaptic density. Loss of SIN3A increases expression of the synaptic scaffold Homer1, alters the metabotropic glutamate receptor 1α (mGluR1α) and mGluR5 dependence of long-term potentiation, and increases activation of ERK in the hippocampus after learning. Our studies define a critical role for corepressors in modulating neural plasticity and memory consolidation and reveal that Homer1/mGluR signaling pathways may be central molecular mechanisms for memory enhancement.
长期记忆依赖于对活动依赖性神经元基因表达的控制，而这种表达是由表观遗传修饰调节的。组蛋白的表观遗传修饰是由两类调节复合物的相反活动协调的：允许性共激活因子和沉默共抑制因子。许多研究工作都集中在共激活因子复合物上，但对于抑制可塑性相关基因表达的共抑制因子复合物却知之甚少。在这里，我们确定了共抑制因子SIN3A在记忆和突触可塑性中的关键作用，表明出生后神经元中Sin3a的缺失增强了海马体的长时程增强和长期情境恐惧记忆。SIN3A调节突触后致密物中编码蛋白质的基因的表达。SIN3A的缺失增加了突触支架蛋白Homer1的表达，改变了长时程增强对代谢型谷氨酸受体1α（mGluR1α）和mGluR5的依赖性，并在学习后增加了海马体中ERK的激活。我们的研究确定了共抑制因子在调节神经可塑性和记忆巩固中的关键作用，并揭示Homer1/mGluR信号通路可能是记忆增强的核心分子机制。
