The Physiology of Extra Synaptic NMDA Receptors

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，并且对于发育期间的正常突触发生也至关重要。许多研究表明，NMDAR激活的结果可以根据受体定位、时间特征和信号大小而广泛变化（Bito等人，1996; Fields等人，1997; Hardingham等人，1999; Chawla和Bading，2001; Hardingham等人，2001 a，B）。本研究的重点是突触外与突触NMDAR的生理作用。培养的神经元研究表明，NMDAR可以作为突触NR 1/NR 2A异聚体和突触外NR 1/NR 2B异聚体存在。这两种受体类型可以与非常不同的细胞过程偶联，其中钙通过突触外NMDAR进入激活细胞死亡机制和LTD而不是LTP（Lu等人，2001; Hardingham等人，2002年）。虽然这些实验提供了有价值的线索可能的空间和功能分离的突触外NMDAR的神经元，这些受体在完整的组织中的存在和生理相关性仍然不清楚。我们的初步结果，这是显着不同的文化测量，表明约40%的NMDAR人口是突触外急性海马切片树突。这表明，在突触前高活动期间，有大量的突触外受体可用于激活。我们的基本假设是，突触外NMDAR参与神经元的相互作用，在病理和生理相关的条件下。这一假设将通过确定突触外NMDAR池的大小、亚基组成和急性海马脑切片中的发育表达来检验。我们将确定条件下，突触外受体可以参与传输和他们的作用，在表达的长时程增强或抑郁症。

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.