MOLECULAR DETERMINANTS OF VISUAL CORTICAL PLASTICITY

环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个提议的核心假设 cGMP在调节突触效能中起着重要作用， 发展和成熟的哺乳动物视觉系统， cGMP由一类环核苷酸门控阳离子介导， 通道和cGMP依赖性蛋白激酶。 本提案的总体假设将用三个 具体目标。首先，表达水平和细胞水平 参与cGMP代谢和cGMP的分子分布 行动将在正常发展和黑暗中衡量饲养 动物这些实验的结果将表明cGMP是否起作用 在所有皮层神经元中，cGMP是否被用作 信使在所有发展阶段，以及是否模式化的视觉输入 改变cGMP第二信使系统。 第二个具体目标将确定cGMP水平是否在视觉 通过测量浓度， 皮质切片中cGMP的浓度 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， 参与cGMP水平的调节和视觉皮层 可塑性。 第三个具体目标将直接测试cGMP是否可以调节 膜特性和突触相互作用的识别视觉 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识别的细胞来测量： 逆行转运或抗体标记。cGMP的作用 将测量对谷氨酸受体激动剂的反应以确定 受体敏感性或脱敏是否改变。最后 cGMP改变皮层神经元之间突触相互作用的能力 将被衡量。使用一系列激动剂和拮抗剂选择性 环核苷酸门控阳离子cGMP依赖性蛋白激酶 通道，将进行实验，以确定途径， cGMP发挥其作用。 总的来说，这个项目将阐明一个重要的第二个功能， 视觉皮层的信使系统，特别是cGMP 可以改变皮层神经元之间的突触相互作用的功效。 从这些实验中获得的信息将有助于理解 正常的信息处理和重要的发展 影响视觉皮层的异常，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.