MECHANISMS OF VISUAL PLASTICITY

视觉可塑性的机制

• 批准号: 6042005
• 负责人: Ary S Ramoa
• 金额: $ 1.23万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6042005
• 关键词: NMDA receptors; amblyopia; antisense nucleic acid; early embryonic stage; electrophysiology; ferrets; gel electrophoresis; immunocytochemistry; molecular cloning; neural plasticity; neural transmission; polymerase chain reaction; receptor expression; receptor sensitivity; synapses; vision disorders; visual cortex; voltage /patch clamp

The mammalian visual system requires experience to develop normally. Lack of sensory experience due to degradation of the visual input of one eye during development may lead to irreversible loss of visual function mediated by this eye. This condition, known as amblyopia, is a major cause of visual disability in children. There is no doubt regarding the substantial scientific and clinical relevance of this type of neural plasticity. However, the cellular and molecular mechanisms underlying this crucial developmental process remain unknown. In recent years much attention has been focused on the N-methyl-D-aspartate (NMDA) subtype of excitatory amino acid receptor because of its proposed role in brain development, learning and memory. Its specific role in visual plasticity has, nevertheless, remained elusive. Recent molecular studies have provided an exciting new opportunity to examine the contribution of the NMDA receptor to visual function and plasticity. These studies have shown that this receptor is composed of different subunit proteins and that different combinations of subunits exhibit distinct functional properties. It is proposed here that developmental changes in subunit composition of the NMDA receptor play a critical role in visual plasticity. A novel approach is proposed to examine this hypothesis. Intracortical infusion of antisense DNA will be used to suppress selected NMDA receptor subunits. The receptors should then be assembled from the remaining subunits. The resultant modifications in functional properties of cortical NMDA receptors will be examined by intracellular recordings in cortical slices maintained living in vitro and the changes in visual responses will be assessed in normal animals as well as in those which were monocularly deprived of vision during antisense treatment. This approach offers several significant advantages over currently used pharmacological procedures, such as the possibility of selectively manipulating individual subunits. Moreover, transgenic animals cannot be used to conduct these experiments, since animals lacking some NMDA receptor subunits are not viable. The results should delineate links between the molecular composition of the NMDA receptor and its functional role in visual cortex. In addition, since molecular interventions may one day be used for therapeutic purposes in visual disorders, these studies may provide a new dimension to our clinical armamentarium at the level of the synapse.

哺乳动物的视觉系统需要经验才能正常发育。 由于视觉输入的退化而缺乏感官体验 眼睛在发育过程中可能会导致不可逆的视觉功能丧失 由这只眼睛来调节。 这种情况，被称为弱视，是一个主要的 儿童视力残疾的原因。 毫无疑问， 这种类型的神经系统的实质性科学和临床相关性 可塑性 然而，细胞和分子机制， 这一重要的发育过程仍不为人所知。 近年来， N-甲基-D-天冬氨酸（NMDA）亚型已引起人们的关注 兴奋性氨基酸受体，因为它在大脑中的作用 发展、学习和记忆。 它在视觉上的特殊作用 然而，可塑性仍然难以捉摸。 最近的分子 研究提供了一个令人兴奋的新机会， NMDA受体对视觉功能和可塑性的贡献。 这些研究表明，这种受体是由不同的 亚基蛋白质和亚基的不同组合表现出 不同的功能特性。 在这里，我们建议发展 NMDA受体亚基组成的变化起着关键作用 在视觉可塑性方面。 提出了一种新的方法来研究这一点 假说. 皮质内输注反义DNA将用于 抑制选定的NMDA受体亚单位。 那么受体应该是 由剩余的子单元组装而成。 由此产生的修改， 皮层NMDA受体的功能特性将通过以下方法进行检查： 在体外保持存活的皮质切片中的细胞内记录 并在正常动物中评估视觉反应的变化 以及那些单眼失明的人， 反义治疗 这种方法提供了几个重要的 与目前使用的药理学方法相比， 选择性地操纵单个亚基的可能性。 此外，委员会认为， 转基因动物不能用于进行这些实验，因为 缺乏某些NMDA受体亚单位的动物不能存活。结果 应该描绘出NMDA的分子组成之间的联系， 受体及其在视皮层中的功能作用。 另外由于 有一天，分子干预可能会用于治疗目的， 视觉障碍，这些研究可能会提供一个新的层面，我们的 突触水平的临床医疗设备。