Genetic Enhancement of Memory and Long-Term Potentiation but Not CA1 Long-Term Depression in NR2B Transgenic Rats

One major theory in learning and memory posits that the NR2B gene is a universal genetic factor that acts as rate-limiting molecule in controlling the optimal NMDA receptor's coincidence-detection property and subsequent learning and memory function across multiple animal species. If so, can memory function be enhanced via transgenic overexpression of NR2B in another species other than the previously reported mouse species? To examine these crucial issues, we generated transgenic rats in which NR2B is overexpressed in the cortex and hippocampus and investigated the role of NR2B gene in NMDA receptor-mediated synaptic plasticity and memory functions by combining electrophysiological technique with behavioral measurements. We found that overexpression of the NR2B subunit had no effect on CA1-LTD, but rather resulted in enhanced CA1-LTP and improved memory performances in novel object recognition test, spatial water maze, and delayed-to-nonmatch working memory test. Our slices recordings using NR2A- and NR2B-selective antagonists further demonstrate that the larger LTP in transgenic hippocampal slices was due to contribution from the increased NR2B-containing NMDARs. Therefore, our genetic experiments suggest that NR2B at CA1 synapses is not designated as a rate-limiting factor for the induction of long-term synaptic depression, but rather plays a crucial role in initiating the synaptic potentiation. Moreover, our studies provide strong evidence that the NR2B subunit represents a universal rate-limiting molecule for gating NMDA receptor's optimal coincidence-detection property and for enhancing memory function in adulthood across multiple mammalian species.

学习与记忆领域的主流理论之一提出，NR2B基因是一类通用遗传因子，可作为限速分子调控多种动物物种中N-甲基-D-天冬氨酸受体（NMDA receptor）的最佳重合检测特性，以及后续的学习与记忆功能。若该理论成立，那么在此前已报道的小鼠物种之外的其他物种中，通过转基因过表达NR2B，是否能够增强记忆功能？为探究这一关键科学问题，本研究构建了在皮层与海马体中过表达NR2B的转基因大鼠，并结合电生理技术与行为学检测手段，研究NR2B基因在NMDA受体介导的突触可塑性及记忆功能中的作用。本研究发现，NR2B亚基的过表达对CA1区长时程抑制（CA1-LTD）无显著影响，反而可增强CA1区长时程增强（CA1-LTP），并在新物体识别实验、空间水迷宫实验以及延迟非匹配工作记忆实验中改善记忆表现。本研究通过使用NR2A与NR2B选择性拮抗剂进行脑片记录实验，进一步证实转基因大鼠海马脑片中增强的LTP，源于过表达的含NR2B的NMDA受体的作用。因此，本研究的遗传学实验结果表明，CA1突触处的NR2B并非长时程突触抑制诱导的限速因子，而是在启动突触增强过程中发挥关键作用。此外，本研究提供了强有力的证据，证明NR2B亚基是一类通用的限速分子，可调控NMDA受体的最佳重合检测特性，并在多种哺乳动物成体中增强记忆功能。