Jacobs Stephanie, Cui Zhenzhong, Feng Ruiben, Wang Huimin, Wang Deheng, Tsien Joe Z
Brain and Behavior Discovery Institute and Department of Neurology, Medical College of Georgia at Georgia Regents University, Augusta, Georgia, United States of America.
Shanghai Institute of Functional Genomics, East China Normal University, Shanghai, China.
PLoS One. 2014 Oct 31;9(10):e111865. doi: 10.1371/journal.pone.0111865. eCollection 2014.
The opening-duration of the NMDA receptors implements Hebb's synaptic coincidence-detection and is long thought to be the rate-limiting factor underlying superior memory. Here, we investigate the molecular and genetic determinants of the NMDA receptors by testing the "synaptic coincidence-detection time-duration" hypothesis vs. "GluN2B intracellular signaling domain" hypothesis. Accordingly, we generated a series of GluN2A, GluN2B, and GluN2D chimeric subunit transgenic mice in which C-terminal intracellular domains were systematically swapped and overexpressed in the forebrain excitatory neurons. The data presented in the present study supports the second hypothesis, the "GluN2B intracellular signaling domain" hypothesis. Surprisingly, we found that the voltage-gated channel opening-durations through either GluN2A or GluN2B are sufficient and their temporal differences are marginal. In contrast, the C-terminal intracellular domain of the GluN2B subunit is necessary and sufficient for superior performances in long-term novel object recognition and cued fear memories and superior flexibility in fear extinction. Intriguingly, memory enhancement correlates with enhanced long-term potentiation in the 10-100 Hz range while requiring intact long-term depression capacity at the 1-5 Hz range.
N-甲基-D-天冬氨酸（NMDA）受体的开放持续时间实现了赫布突触巧合检测，长期以来一直被认为是卓越记忆背后的限速因素。在这里，我们通过测试“突触巧合检测时间持续”假说与“GluN2B细胞内信号结构域”假说，来研究NMDA受体的分子和遗传决定因素。相应地，我们生成了一系列GluN2A、GluN2B和GluN2D嵌合亚基转基因小鼠，其中C末端细胞内结构域被系统地交换并在前脑兴奋性神经元中过表达。本研究中呈现的数据支持第二个假说，即“GluN2B细胞内信号结构域”假说。令人惊讶的是，我们发现通过GluN2A或GluN2B的电压门控通道开放持续时间是足够的，并且它们的时间差异很小。相比之下，GluN2B亚基的C末端细胞内结构域对于长期新颖物体识别和线索恐惧记忆中的卓越表现以及恐惧消退中的卓越灵活性是必要且充分的。有趣的是，记忆增强与10 - 100赫兹范围内增强的长时程增强相关，同时需要在1 - 5赫兹范围内具有完整的长时程抑制能力。
