cAMP Signaling Cascades in Sensory Map Development

点击翻译按钮获取中文摘要

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.