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

谷氨酸代谢性受体在脊髓突触可塑性中的作用现已证实，初级传入纤维在脊髓浅背角(SDH)使用谷氨酸作为主要的快速兴奋性递质，SDH是感觉信息从外周受体传递到大脑的第一个调制部位。谷氨酸通过两大类受体发挥作用，离子通道连接(离子通道)受体(AMPA/Kainate和NMDA受体)和代谢性受体(MGluRs)，它们通过G蛋白耦合到细胞内的第二信使级联。I组mGluRs(mGluR1和5个亚型)由SDH中的神经元表达，但它们在突触功能中的作用以及在脊髓躯体感觉传递和突触可塑性中的作用尚不清楚。最近与这些受体结合的配体的发展，以及缺乏mGluR1或mGluR5受体的突变小鼠的出现，提供了一种手段来表征它们在调节快慢兴奋性突触传递中可能发挥的重要作用，包括我们最近的初步证据所表明的诱导突触效能的长期变化。本研究的两个主要目的是：1)研究I组mGluRs通过ICAN(非选择性钙依赖阳离子通道)参与SDH区初级传入诱发的慢兴奋性突触电位(SEPSP)的产生；2)研究激活I组mGluRs对AMPA和NMDA受体介导的感觉传递的调节作用。本研究将结合细胞内和全细胞膜片钳记录、钙离子成像和药理学技术，研究I组mGluR激活在幼年大鼠和缺失mGlu1或5受体突变小鼠脊髓切片内SDH神经元突触传递和可塑性中的作用。阐明I组mGluR在SDH区的生理作用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，特别是对突触可塑性和伤害性感受的重要一步。

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.