| Learning and memory, as high function of brain, are critical to mammalian especially for human survival. Increasing evidences indicate thatN-methyl-D-aspartate (NMDA) receptor, especially the NR2B subunit, plays a crucial role in synaptic plasticity, learning and memory. In 1999, Dr. Tsien and his colleagues at Princeton University (USA) breached the limitation of gene technique and established the transgenic mouse that overexpressed NR2B subunit in forebrain. This transgenic mouse showed the enhancement in activation of NMDA receptor, NMDA receptor channel open duration, and synaptic potentiation in response to high frequency stimulation in vitro. In addition, the mouse exhibited superior ability in learning and memory in various behavioral tasks (such as water maze, cued and contextual fear conditioning). These results indicated that NR2B subunit was a key switch for synaptic plasticity, learning and memory in mouse. However, whether NR2B subunit represents a universal molecular switch in gating the level of synaptic plasticity and memory function in the adult brain is still unknown. In another word, is the NR2B subunit also critical for synaptic plasticity and learning memory in the different animal model other than mice? We used electrophysiological and behavioral techniques to systematically analyze the effect of NR2B subunit overexpression and reference memory. The main objectives are as follows:1. Investigation of synaptic transmission in transgenic rats1.1 The basic synaptic transmissionWe investigated the basic transmission function of hippocampal Schaffer collateral-CA1 region in transgenic model rats using the brain slice field potential recording technique. The results from the Input-Output curve and Paired pulse facilitation indicated that postsynaptic AMPA receptors and presynaptic functions in NR2B transgenic rats were normal.1.2 The synaptic plasticity mediated by NMDA receptorWe used the same technique to investigate the effect of NR2B overexpression specific in forebrain on synaptic plasticity in hippocampal Schaffer collateral-CA1 region. The results indicated that the NMDA receptor-dependent LTP was significantly enhanced. Furthermore, we used NMDA receptor NR2A subunit and NR2B subunit antagonists to study the role of NR2A and NR2B subunits in NMDA receptor mediated LTP. The results showed that LTPs from both the transgenic and wild-type rats were attenuated by NR2A or NR2B subunit antagonist. Especially, LTP from the transgenic rat was significantly larger than that from wild type rat when NR2A subunit antagonist was delivered. These results indicated that both the NR2A and NR2B subunits participated in the formation of NMDA receptor mediated LTP. The overexpression of NR2B subunit could enhance the NMDA receptor-dependent LTP. On the other hand, there was no significant difference between NR2B transgenic and wild-type rats on formation of LTD (Long-term depression). When using the NR2B subunit antagonist, the LTD was decreased, which was not significant.2. Investigation of behavioral tasks in transgenic ratsNumerous studies have demonstrated that the NMDA receptor dependent synaptic plasticity is associated with learning and memory. To investigate the relationship between overexpression of NR2B subunit in forebrain and forebrain dependent learning and memory function, we used T-maze DNMS (The delayed non match-to-sample) and water maze tasks to study the spatial working and reference memory in rats. The results indicated that the transgenic rats had superior spatial working and reference memory. Thus, the overexpression of NR2B subunits in forebrain also could improve the learning and memory function in rats.In summary, our electrophysiological analyses show overexpression of NR2B subunit in forebrain of rats led to the enhancement of NMDAR-mediated LTP and better learning and memory as observed in mice. We conclude that the NR2B subunit may serve as a crucial gating switch for controlling learning and memory functions across different animal species.
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