Molecular Determinants of Visual Cortical Plasticity

描述：环状GMP是中枢神经系统中重要的第二信使。一直以来 显示在突触前和突触后部位有特定的动作 导致突触效能的短期戏剧性改变。中环 这一提议的假设，即这些行动协同作用，影响 信息通过视觉皮质流动，类似动作在 更持久的可塑性，将通过四个具体目标进行测试。在……里面 第一个目的，cGMP增强NMDA受体反应的机制 将会被研究。将使用电生理测量来证实 升高cGMP可降低受体的脱敏作用。重组NMDA受体 亚基，包括那些在出生后发育中发生变化的亚基，将被用来 确定cGMP是否导致一个或多个亚基的直接磷酸化。 最后，cGMP在一些大脑皮层神经元诱导的小去极化将 进行研究，以确定这些操作如何组合在一起以选择性地增加 通过NMDA受体的谷氨酸反应的比例。这个 第二个目标是研究cGMP可以显著抑制 突触前终末的皮质GABA能反应。一种组合 将进行电生理测量和钙成像研究 来验证cGMP水平升高会导致抑制 质膜电压依赖性钙通道与内质网 网状InsP3受体钙通道。此外，cGMP介导的血管紧张素转换酶的作用 将测试突触小泡的下游动员。 第三个目的是研究cGMP诱导膜去极化的机制。 在大脑皮层神经元。过去的研究表明，这可以通过 环核苷酸门控阳离子通道。BCG渠道，负责ih 在许多细胞类型中，电流也受环核苷酸的调节。这个 这些通道在不同皮质细胞中的发育和分布将 被研究。CGMP和cAMP对这些通道的影响将被研究以 确定激活如何改变皮质细胞的突触反应。 最后，我们将使用刺激范式来研究cGMP的作用。 更持久的突触可塑性。这样的实验将测试 假设短期调制是机械性地研究的 建议对于更持久的增强或抑制也很重要 皮质突触反应。这项提议是一个连贯的计划，将 在分子水平上解释重要的第二信使的活动，并展示如何 它影响视觉中单个细胞和细胞组合的生理学 大脑皮层。

DESCRIPTION: Cyclic GMP is a vital second messenger in the CNS. It has been shown to have specific actions at presynaptic and postsynaptic sites that induce dramatic short-term alterations in synaptic efficacy. The central hypotheses of this proposal, that these actions act synergistically to affect information flow through visual cortex and that similar actions play a role in longer lasting forms of plasticity, will be tested with four specific aims. In the first aim, the mechanism by which cGMP enhances NMDA receptor responses will be studied. Electrophysiological measurements will be used to confirm that elevation of cGMP decreases receptor desensitization. Recombinant NMDA receptor subunits, including those that change in postnatal development, will be used to determine whether cGMP causes direct phosphorylation of one or more subunits. Finally, the small depolarization induced in some cortical neurons by cGMP will be studied to determine how these actions combine to increase selectively the proportion of the glutamate response passing through the NMDA receptor. The second aim will study the mechanism by which cGMP can dramatically inhibit cortical GABAergic responses at the presynaptic terminal. A combination of electrophysiological measurements and calcium imaging studies will be carried out to test the hypothesis that elevation of cGMP levels leads to inhibition of both plasma membrane voltage-dependent calcium channels and the endoplasmic reticulum InsP3 receptor calcium channel. In addition, cGMP-mediated effects on the downstream mobilization of synaptic vesicles will be tested. The third aim will study the mechanism of cGMP-induced membrane depolarization in cortical neurons. Past work has shown that this can occur through cyclic-nucleotide gated cation channels. Bcng channels, responsible for the Ih current in many cell types, are also regulated by cyclic nucleotides. The development and distribution of these channels in different cortical cells will be studied. The effects of cGMP and cAMP on these cannels will be studied to determine how activation can alter synaptic responses of cortical cells. Finally, actions of cGMP will be studied using stimulus paradigms that cause longer lasting forms of synaptic plasticity. Such experiments will test the hypothesis that the short-term modulation studied mechanistically in this proposal are also important for longer lasting potentiation or depression of cortical synaptic responses. This proposal is a coherent program that will explain actions of a vital second messenger at the molecular level and show how it affects the physiology of individual cells and cell assemblies within visual cortex.