cAMP Signaling Cascades in Sensory Map Development

描述（由申请人提供）：在皮层感觉图中，丘脑皮层传入（TCA）以有组织的阵列将外周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有效的突触传递和快速适应重复刺激。如果这条通路功能失调，大脑就无法解释感官线索。然而，皮质地图的发展和这一途径的功能特性的机制在很大程度上是未知的。在无桶小鼠中，钙/钙调素激活的腺苷酸环化酶1（AC 1）的功能缺失突变体，TCA到达其皮质靶点，但未能形成桶图，即小鼠体感图。此外，TCA在无桶小鼠中不能正常成熟，这表明AC 1介导的信号通路不仅是建立TCA正确结构所必需的，而且也是TCA本身功能发育所必需的。有趣的是，TCA释放机制的功能成熟与桶图的形成同时发生。已经表明，AC 1介导长期突触增强，并且是学习和记忆所必需的。我们假设，在皮层地图形成过程中，自然发生的突触增强由AC 1介导，利用相同的机制，突触前起源的突触可塑性。此外，我们假设AC 1调节突触囊泡蛋白和活性区蛋白之间的功能相互作用，以促进神经递质的释放。将采用电生理学、药理学、解剖学和生物化学技术的组合来比较野生型和无桶TCA的功能、结构和生物化学特性。在感觉图形成过程中，假定的AC 1靶点RIM和突触蛋白（在本项目中鉴定）的作用将通过检查功能丧失突变小鼠的桶图形成来研究。这是我们第一次能够在分子水平上将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.