cAMP Signaling Cascades in Sensory Map Development

描述(申请人提供)：在皮质感觉图中，丘脑皮质传入(TCA)以有组织的阵列将外围感觉传输到不同的神经元模块中，以提供外部感觉世界的地形图表示。成熟TCA的专门释放功能允许高效的突触传递和对重复刺激的快速适应。如果这条通路功能失调，大脑就不能解释感觉提示。然而，大脑皮层MAP形成的潜在机制和这一途径的功能特性在很大程度上是未知的。在无桶小鼠中，作为钙/钙调蛋白激活的腺酰环化酶1(AC1)的功能丧失突变体，TCA到达了它们的皮质目标，但未能形成桶状图，即小鼠的体感图。此外，TCA在无桶小鼠中不能正常成熟，这表明AC1介导的信号通路不仅对于建立TCA的正确架构是必要的，而且对于TCA本身的功能发育也是必要的。有趣的是，TCA释放机制的功能成熟与桶状MAP的形成同时发生。已有研究表明，AC1介导长时程突触增强，是学习和记忆所必需的。我们假设，在皮质映射形成过程中，AC1介导的自然发生的突触增强使用了相同的机制来支持突触前起源的突触可塑性。此外，我们假设AC1调节突触小泡蛋白和活动区蛋白之间的功能相互作用，以促进神经递质的释放。将结合电生理学、药理学、解剖学和生化技术来比较野生型和无桶三氯甲烷的功能、结构和生化特性。假定的AC1靶标RIM和突触素(在本项目中确定)在感觉地图形成中的作用将通过检查其功能丧失的突变小鼠的桶状地图形成来研究。我们将第一次能够在分子水平上将大脑皮层地图的发展与感觉功能联系起来。

DESCRIPTION (provided by applicant): In cortical sensory maps, thalamocortical afferents (TCAs) transmit peripheral sensations in organized arrays into distinct neuronal modules to provide a topographic representation of the external sensory world. The specialized release features of mature TCAs allow efficient synaptic transmission and rapid adaptation to repetitive stimuli. If this pathway is dysfunctional, the brain cannot interpret sensory cues. Yet, the mechanisms underlying the development of the cortical map and the functional properties of this pathway is largely unknown. In barrelless mice, a loss-of-function mutant of calcium/calmodulin-activated adenylyl cyclase 1 (AC1), TCAs reach their cortical target but fail to form a barrel map, the mouse somatosensory map. In addition, TCAs do not mature properly in barrelless mice, which suggests that AC1-mediated signaling pathways are required not only for establishing the correct architecture of the TCAs but also for the functional development of the TCA itself. Interestingly, the functional maturation of the TCA release machinery occurs concurrently with the formation of the barrel map. It has been shown that AC1 mediates long-term synaptic enhancement and is required for learning and memory. We hypothesize that the naturally occurring synaptic enhancement mediated by AC1 during cortical map formation utilize the same mechanisms underlying presynaptic-origin synaptic plasticity. Further, we posit that AC1 modulates the functional interactions among synaptic vesicle proteins and active zone proteins to facilitate neurotransmitter release. A combination of electrophysiological, pharmacological, anatomical, and biochemical techniques will be employed to compare the functional, structural, and biochemical properties of wild type and barrelless TCAs. The role of the putative AC1 targets RIM and Synapsin (identified in this project) during sensory map formation will be studied by examining barrel map formation in their loss-of-function mutant mice. For the first time we will be able to correlate cortical map development with sensory function at a molecular level.