EXCITATORY AMINO ACIDS--ROLE IN CNS DISORDERS

我们项目的长期目标是研究 在兴奋性氨基酸（EAA）突触，并利用这一知识， 提供：（1）更深入地了解CNS在健康中的功能， 疾病在细胞和系统水平，和（2）新的治疗 治疗CNS功能障碍的机会。 实现这一 为了实现这一目标，将采用一系列策略，这些策略如下：（1）新的 将寻求有关EAA受体亚型（或亚型）信息 负责调节特定功能和/或病理状态 在确定的CNS部位使用药理学工具，特异性抗体 EAA亚型，和EAA受体特异性cDNA探针;这里的重点 将在EAA离子型和代谢型受体上;（2）新的 将寻求有关内部发生的一连串事件的信息， 神经元（和神经胶质）激活后的特定EAA受体;（3）新的 将寻求关于细胞和功能后果的信息 NMDA和AMPA的变构调节位点的改变 受体亚型，特别是，对激活变构位点 对AMPA受体复合物与环噻嗪;（4）新的信息将 EAA介导的兴奋性突触前机制 神经传递和神经毒性，包括关于 谷氨酸释放（使用BW 1003 C87）、摄取（使用L-Trans-PDC）、NAAG 释放和细胞外水解产生谷氨酸和NAAG， 谷氨酸作为假定的突触前抑制剂，通过抑制 腺苷酸环化酶;（5）将寻求新的信息， 可能调节EAA释放的其他神经递质系统 或NAAG，或者可以提供调节突触后效应的突触后效应。 监管局的回应;及（6）监管局将提供新资料， 离子型和代谢型受体之间的重要相互作用 存在，以及这种相互作用对突触传递的影响。 通过 利用这六个研究策略，我们将获得更深入的 了解CNS EAA突触传递在健康和 疾病，并将增加治疗的机会， CNS功能紊乱。

The long range goal of our program project is to study events that occur at the excitatory amino acid (EAA) synapse and to use this knowledge to provide: (1) more in-depth understanding of CNS functions in health and disease at both the cellular and systems level, and (2) new therapeutic opportunities in treating disorders of CNS function. To achieve this goal, a set of strategies will be used and these are as follows: (1) New information will be sought on EAA receptor subtype (or subtypes) responsible for mediating a specific function and/or pathological state at identified CNS sites using pharmacological tools, specific antibodies to EAA subtypes, and EAA receptor specific cDNA probes; the focus here will be on both EAA ionotropic and metabotropic receptors; (2) New information will be sought on the cascade of events that occur inside neurons (and glia) after activation of specific EAA receptors; (3) New information will be sought on the cellular and functional consequences of alterations in the allosteric modulatory sites of the NMDA and AMPA receptor subtypes, especially, on the activation of an allosteric site on the AMPA receptor complex with cyclothiazide; (4) New information will be sought on the presynaptic mechanisms in EAA-mediated excitatory neurotransmission and neurotoxicity including information on the role of glutamate release (using BW1003C87), uptake (using L-Trans-PDC), NAAG release and extracellular hydrolysis to produce glutamate, and NAAG and glutamate as putative presynaptic inhibitors acting by inhibiting adenylate cyclase; (5) New information will be sought on the role of other neurotransmitter systems that may regulate the release of EAA(s) or NAAG, or that may provide a post-synaptic effect which modulates the EAA response; and (6) New information will be sough on whether significant interactions between ionotropic and metabotropic receptors exist, and the impact of such interactions on synaptic transmission. By utilizing these six research strategies we will gain a more in-depth understanding of the role of CNS EAA synaptic transmission in health and disease, and will increase the therapeutic opportunities for treating disorders of CNS function.