Involvement of Glutamate Metabotropic Receptors in Synaptic Plasticity in the Spinal Cord

谷氨酸代谢型受体参与脊髓突触可塑性

• 批准号: 0200051
• 负责人: Mirjana Randic
• 金额: $ 33万
• 依托单位: Iowa State University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0200051&HistoricalAwards=false
• 关键词: Involvement; Glutamate; Metabotropic; Receptors; Synaptic

INVOLVEMENT OF GLUTAMATE METABOTROPIC RECEPTORS IN SYNAPTIC PLASTICITY IN THE SPINAL CORDIt is now well established that the primary afferent fibers use glutamate as a principal fast excitatory transmitter in the superficial dorsal horn (SDH) of the spinal cord, the first modulatory site in the relay of sensory information from the peripheral receptors to the brain. Glutamate acts through two broad classes of receptors, ion-channel-linked (ionotropic) receptors (AMPA/kainate and NMDA receptors) and metabotropic receptors (mGluRs), which couple via G-proteins to the intracellular second messenger cascades. Group I mGluRs (mGluR1 and 5 subtypes) are expressed by neurons in the SDH, but their roles in synaptic function, and contribution to spinal somatosensory transmission and synaptic plasticity, have yet to be elucidated. The recent development of ligands that bind specifically to these receptors, and availability of mutant mice lacking mGluR1 or mGluR5 receptors, has provided means of characterizing the important roles they may play in tuning of fast and slow excitatory synaptic transmission, including the induction of long-term changes in synaptic efficacy, as suggested by our recent preliminary evidence.Two major objectives in the proposal are: 1) to study involvement of Group I mGluRs via ICAN (non-selective Ca2+-dependent cation channels) in the generation of primary afferent-evoked slow excitatory synaptic potential (sEPSP) in the SDH region; and 2) to study regulation of AMPA and NMDA receptor-mediated sensory transmission by activation of Group I mGluRs. A combination of intracellular and whole-cell patch-clamp recordings, Ca2+ imaging, and pharmacological techniques will be employed to study the involvement of Group I mGluR activation in synaptic transmission and plasticity in SDH neurons within spinal cord slices prepared from young rats and mutant mice lacking mGlu1 or 5 receptors.Delineating the physiological roles of the Group I mGluRs in the SDH region, and cellular and molecular mechanisms underlying their actions, is an important step toward understanding of implications of glutamate-mediated transmission in the spinal cord DH synaptic function, but in particular for synaptic plasticity and nociception.

谷氨酸代谢型受体在脊髓突触可塑性中的作用现在已经确定，初级传入纤维使用谷氨酸作为脊髓背角浅层（SDH）中的主要快速兴奋性递质，脊髓背角浅层是将感觉信息从外周受体传递到大脑的第一个调节部位。 谷氨酸通过两大类受体起作用，离子通道连接的（离子型）受体（AMPA/红藻氨酸和NMDA受体）和代谢型受体（mGluR），它们通过G蛋白偶联到细胞内第二信使级联。 I组mGluR（mGluR 1和5亚型）由SDH中的神经元表达，但它们在突触功能中的作用以及对脊髓体感传递和突触可塑性的贡献尚未阐明。 与这些受体特异性结合的配体的最新发展，以及缺乏mGluR 1或mGluR 5受体的突变小鼠的可用性，提供了表征它们在调节快和慢兴奋性突触传递中可能发挥的重要作用的方法，包括诱导突触功效的长期变化，正如我们最近的初步证据所建议的那样。1）研究I组mGluRs通过ICAN（非选择性Ca 2+依赖性阳离子通道）参与SDH区域中初级传入诱发的慢兴奋性突触电位（sEPSP）的产生;和2）研究通过激活I组mGluRs调节AMPA和NMDA受体介导的感觉传递。 将采用细胞内和全细胞膜片钳记录、Ca 2+成像和药理学技术的组合来研究I组mGluR活化在从缺乏mGlu 1或5受体的年轻大鼠和突变小鼠制备的脊髓切片内SDH神经元中的突触传递和可塑性中的参与。以及其作用的细胞和分子机制，是理解谷氨酸介导的传递在脊髓DH突触功能中的意义的重要一步，特别是对于突触可塑性和伤害感受。