The Physiology of Extra Synaptic NMDA Receptors

描述(申请人提供)：N-甲基-D-天冬氨酸受体(NMDAR)的激活可以导致长期和短期的可塑性，促进细胞存活，启动细胞死亡，也是发育过程中正常突触发生的关键。许多研究表明，NMDAR激活的后果可能因受体定位、时间特征和信号大小而有很大不同(Bito等人，1996；Fields等人，1997；Hardingham等人，1999；Chawla和Bding，2001；Hardingham等人，2001a，b)。这项研究的重点是突触外NMDAR与突触NMDAR的生理作用。培养的神经元研究表明，NMDAR可以以突触NR1/NR2A异构体和突触外NR1/NR2B异构体的形式存在。这两种受体类型可能耦合到非常不同的细胞过程，通过突触外NMDAR的钙内流激活细胞死亡机制和LTP(Lu等人，2001；Hardingham等人，2002)。尽管这些实验为突触外NMDAR在神经元中可能的空间和功能隔离提供了有价值的线索，但这些受体在完整组织中的存在和生理相关性仍不清楚。我们的初步结果与培养测量结果显著不同，表明在急性海马片树突中，大约40%的NMDAR群体是突触外的。这表明，在高突触前活动期，有大量的突触外受体可供激活。我们的基本假设是，突触外NMDAR在病理和生理相关的条件下参与神经元的相互作用。这一假说将通过测定突触外NMDAR池的大小、亚单位组成和急性海马脑片的发育表达来验证。我们将确定突触外受体参与传递的条件，以及它们在长时程增强或抑制表达中的作用。

DESCRIPTION (provided by applicant): N-methyl-D-aspartate receptor (NMDAR) activation can result in both long and short-term plasticity, promote cell survival, initiate cell death, and is also critical for normal synaptogenesis during development. A number of studies suggest that the consequences of NMDAR activation can vary widely depending on receptor localization, temporal characteristics, and size of the signal (Bito et al., 1996; Fields et al., 1997; Hardingham et al., 1999; Chawla and Bading, 2001; Hardingham et al., 2001a, b). The focus of this study is the physiological role of extrasynaptic vs. synaptic NMDARs. Cultured neuron studies have suggested that NMDARs can exist as synaptic NR1/NR2A heteromers and extrasynaptic NR1/NR2B heteromers. These two receptor types may be coupled to very different cellular processes, with calcium entry through extrasynaptic NMDARs activating cell death mechanisms and LTD rather than LTP (Lu et al., 2001; Hardingham et al., 2002). Although these experiments have provided valuable clues about possible spatial and functional segregation of extrasynaptic NMDARs in neurons, the existence and physiological relevance of these receptors in intact tissue remains unclear. Our preliminary results, which are significantly different from culture measurements, suggest that approximately 40% of the NMDAR population is extrasynaptic in acute hippocampal slice dendrites. This indicates that there is a large pool of extrasynaptic receptors available for activation during periods of high presynaptic activity. Our underlying hypothesis is that extrasynaptic NMDARs participate in neuronal interactions under pathological and physiologically relevant conditions. This hypothesis will be tested by determining the size of the extrasynaptic NMDAR pool, subunit composition, and developmental expression in acute hippocampal brain slices. We will determine the conditions under which extrasynaptic receptors can participate in transmission and their role in the expression of long-term potentiation or depression.