Experience-dependent GluR trafficking in visual cortex

视觉皮层中依赖于经验的 GluR 运输

• 批准号: 6620732
• 负责人: Elizabeth Mary Quinlan
• 金额: $ 14.8万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6620732
• 关键词: AMPA receptors; NMDA receptors; autoradiography; binocular vision; biological signal transduction; electrodes; experience; glutamate receptor; laboratory rat; neurotransmitter transport; protein biosynthesis; synapses; visual cortex; western blottings

Despite the importance of visual experience in the normal and pathological development of the visual cortex, the molecular mechanisms by which visual activity induces long-lasting changes in the function of cortical synapses have not been defined. The highly modifiable synapses between excitatory neurons in the mammalian visual cortex use glutamate as a neurotransmitter. As the primary effectors of synaptic glutamate release, changes in the number and/or function of post-synaptic glutamate receptors (GluRs) are likely to dramatically effect synaptic strength. This proposal uses binocular and monocular deprivation paradigms to regulate the strength of synaptic connections in the rat visual cortex, and tests the hypothesis that an experience-induced increase in synaptic strength is mediated by delivery of GluRs, while a deprivation-induced decrease in synaptic strength is due to the removal of synaptic GluRs. Analysis of GluR levels is performed in synatoneurosomes, a subcellular fraction which is enriched for intact, metabolically active glutamatergic synapses. The power of this procedure is revealed by the observation that levels of synaptoneurosomal GluRs are highly correlated with changes in the physiological and pharmacological response properties of synaptic GluRs, and in fact are highly predictive of changes in synaptic strength. The role of synaptic protein synthesis in the long-term experience- dependent maintenance of synaptic GluR levels will also be examined in vivo, and in isolated metabolically active synaptic profiles in vitro. Bidirectional, activity-dependent control of synaptic GluR composition would represent a novel mechanism for the regulation of synaptic efficacy in the developing visual cortex, and identify potential targets (GluR or GluR trafficking proteins) for pharmacological intervention, especially in the case of severe, therapy-resistant amblyopia.

尽管视觉经验在视觉皮层的正常和病理发展中的重要性，但尚未定义视觉活动诱导皮质突触功能的长期变化的分子机制。哺乳动物视觉皮层中兴奋性神经元之间的高度修改突触使用谷氨酸作为神经递质。作为突触谷氨酸释放的主要效应因子，突触后谷氨酸受体（GLURS）的数量和/或功能的变化可能会显着影响突触强度。该提案使用双眼和单眼剥夺范式来调节大鼠视觉皮层中突触连接的强度，并检验了以下假设：经验诱导的突触强度的增加是通过粘附的递送而介导的，而剥夺诱导的突触强度的降低是由于突触的降低而导致的。 GLUR水平的分析是在Synatoneurosomes中进行的，Synatoneurosomes是一种亚细胞分数，该分数富含完整的，代谢活性的谷氨酸能突触。通过观察到，突触肌体胶水的水平与突触胶的生理和药理反应特性的变化高度相关，并且实际上可以高度预测突触强度的变化，从而揭示了该过程的功能。突触蛋白合成在长期经验 - 依赖性的突触Glur水平的维持中的作用也将在体内进行检查，并在体外进行了分离的代谢活性突触特征。双向，活动依赖性控制突触GLUR组成将代表一种调节发育中的视觉皮层中突触功效的新机制，并确定药理学干预的潜在靶标（Glur或Glur运输蛋白），尤其是在严重的，治疗，治疗，抗药性抗药性的抗药性抗药性的情况下。