MOLECULAR DETERMINANTS OF VISUAL CORTICAL PLASTICITY

环状GMP是许多组织中重要的第二信使，包括 中枢神经系统。这是这一提议的中心假设 提示cGMP在脑内突触效应的调节中起重要作用。 发育和成熟的哺乳动物的视觉系统，以及 CGMP是由一类环核苷酸门控阳离子介导的 通道和cGMP依赖的蛋白激酶。 这项提议的总体假设将通过三个方面进行检验 明确的目标。在第一，表达水平和细胞 CGMP代谢和cGMP代谢相关分子的分布 行动将在正常发育期间和黑暗中被测量 动物。这些实验的结果将表明cGMP是否起作用 在所有皮质神经元中也是如此，无论cGMP作为一种 Messenger在开发的所有阶段以及是否图案化的视觉输入 改变cGMP第二信使系统。 第二个具体目标将决定cGMP水平是否在视觉上 大脑皮质受神经活动的调节，通过测量浓度 用药后皮质脑片中cGMP含量的变化 神经递质激动剂和拮抗剂。这些实验将集中于 谷氨酸、乙酰胆碱和去甲肾上腺素，因为这些 参与调节cGMP水平和视觉皮质 可塑性。 第三个具体目标将直接测试cGMP是否能够调制 识别视觉的细胞膜特性和突触相互作用 皮质神经元。CGMP对膜的直接和间接作用 电导将通过记录由以下标识的单元来测量 逆行运输或抗体标记。CGMP对血管内皮细胞生长的影响 对谷氨酸受体激动剂的反应将被测量以确定 受体的敏感性或脱敏是否发生改变。最后， CGMP改变皮层神经元间突触相互作用的能力 将会被测量。选择性使用一系列激动剂和拮抗剂 环核苷酸门控阳离子cGMP依赖的蛋白激酶 渠道，将进行实验，以确定途径通过 CGMP发挥其作用。 总体而言，这个项目将阐明一个重要的第二个 视皮层中的信使系统，特别是cGMP 可以改变大脑皮层神经元之间突触相互作用的效果。 从这些实验中获得的信息将提高人们的理解 正常的信息处理和重要的发展 影响视觉皮质的异常，如弱视和斜视。

Cyclic GMP is an important second messenger in many tissues including the Central Nervous System. It is the central hypothesis of this proposal that cGMP plays an important role in regulating synaptic efficacy in the developing and mature mammalian visual system and that the actions of cGMP are mediated both by a class of cyclic nucleotide gated cation channels and by cGMP-dependent protein kinases. The overall hypothesis of this proposal will be tested with three specific aims. In the first, the levels of expression and cellular distribution of molecules involved in both cGMP metabolism and cGMP actions will be measured during normal development and in dark-reared animals. The results of these experiments will indicate whether cGMP acts in the same way in all cortical neurons, whether cGMP is used as a messenger at all stages of development and whether patterned visual input alters the cGMP second messenger system. The second specific aim will determine whether cGMP levels in visual cortex are regulated by neural activity by measuring the concentrations of cGMP in cortical slices following treatment with selected neurotransmitter agonists and antagonists. These experiments will focus on glutamate, acetylcholine and noradrenaline because these have been implicated in the regulation of cGMP levels and in visual cortical plasticity. The third specific aim will test directly whether cGMP can modulate membrane properties and synaptic interactions of identified visual cortical neurons. Direct and indirect effects of cGMP on membrane conductances will be measured by recording from cells identified by retrograde transport or antibody labeling. The effects of cGMP on responses to glutamate receptor agonists will be measured to determine whether receptor sensitivity or desensitization is altered. Finally, the ability of cGMP to alter synaptic interactions between cortical neurons will be measured. Using a series of agonists and antagonists selective for cGMP-dependent protein kinases of cyclic nucleotide gated cation channels, experiments will be carried out to determine the pathway by which cGMP exerts its effects. Overall, this project will elucidate the functions of an important second messenger system in visual cortex, particularly the ways in which cGMP can alter the efficacy of synaptic interactions between cortical neurons. The information gained from these experiments will improve understanding of normal information processing and of important developmental abnormalities that affect visual cortex such as amblyopia and strabismus.