The Physiology of Extra Synaptic NMDA Receptors

突触外 NMDA 受体的生理学

• 批准号: 7047251
• 负责人: DIANA Leslie PETTIT
• 金额: $ 18.67万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-07 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7047251
• 关键词: NMDA receptors; physiology; receptor

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.

描述（由申请人提供）：N-甲基-D-天冬氨酸受体（NMDAR）激活可导致长期和短期可塑性，促进细胞存活，启动细胞死亡，并且对于发育过程中的正常突触发生也至关重要。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差异（Bito 等，1996；Fields 等，1997；Hardingham 等，1999；Chawla和巴丁，2001；Hardingham 等人，2001a，b)。本研究的重点是突触外 NMDAR 与突触内 NMDAR 的生理作用。培养神经元研究表明，NMDAR 可以作为突触 NR1/NR2A 异聚体和突触外 NR1/NR2B 异聚体存在。这两种受体类型可能与非常不同的细胞过程耦合，钙通过突触外 NMDAR 进入激活细胞死亡机制和 LTD 而不是 LTP（Lu 等，2001；Hardingham 等，2002）。尽管这些实验为神经元中突触外 NMDAR 可能的空间和功能分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着不同，表明大约 40% 的 NMDAR 群体位于急性海马切片树突中的突触外。这表明在高突触前活动期间有大量突触外受体可用于激活。我们的基本假设是突触外 NMDAR 参与病理和生理相关条件下的神经元相互作用。该假设将通过确定急性海马脑切片中突触外 NMDAR 池的大小、亚基组成和发育表达来检验。我们将确定突触外受体参与传递的条件及其在长时程增强或抑制表达中的作用。