QUANTITATIVE STUDY OF PRESYNAPTIC FACILITATION

描述（由申请人提供）：突触有效性的变化是神经元网络存储和检索信息的能力的基础，是学习和记忆的细胞水平表示。突触可塑性的一种形式是易化，这是一种突触在重复使用后变得瞬时更有效的现象。易化的经典解释是神经重复刺激增加突触前释放位点的Ca 2+浓度，这反过来又增加了每个位点释放囊泡的概率。然而，最近很明显，这种解释是不完整的。我们最近的研究表明，突触囊泡数量的变化也有助于易化。我们建议定量研究突触前机制如何调节可释放的囊泡池影响促进。突触蛋白是一类神经元特异性磷酸化蛋白，调节囊泡与肌动蛋白丝的结合，从而控制囊泡的可释放性。与建议的可释放的囊泡池在促进作用一致，我们最近已经证明，递质的释放和促进调节突触蛋白中的Ca 2+依赖的方式。在本申请中，我们建议定量研究突触蛋白如何调节突触前囊泡循环，募集囊泡在可释放池，从而不同形式的促进。我们的建议依赖于实验和建模的结合，因为突触前末梢不容易接近实验操作，所有的囊泡池不能精确测量。我们的总体方法是研究突触蛋白对囊泡池的调节，定量模拟囊泡池的动态，并通过其解释不同促进形式及其突触蛋白调节的能力来验证建模。所有开发的计算算法将提供给其他学者。

DESCRIPTION (provided by applicant): Changes in the effectiveness of synapses underlie the ability of neuronal networks to store and retrieve information, the cellular level representation of learning and memory. One form of synaptic plasticity is facilitation, a phenomenon by which a synapse becomes transiently more effective following repeated use. The classical interpretation of facilitation has been that nerve repetitive stimulation increases Ca2+ concentration at presynaptic release sites, which in turn increases the probability of each site to release a vesicle. However, more recently it became clear that this explanation is incomplete. We have recently shown that changes in the number of synaptic vesicles properly activated to be released (the releasable pool of vesicles) also contribute to facilitation. We propose to investigate quantitatively how the regulation of the releasable pool of vesicles by presynaptic machinery affects facilitation. Synapsins, a family of neuron specific phosphoproteins, regulate binding of vesicles to actin filaments and thereby control availability of vesicles to become releasable. Consistently with the proposed role of the releasable vesicle pool in facilitation, we have recently demonstrated that transmitter release and facilitation are regulated by synapsin in a Ca2+-dependent manner. In the present application we propose to investigate quantitatively how synapsin regulates presynaptic vesicle cycling, recruitment of vesicles in the releasable pool, and thereby different forms of facilitation. Our proposal relies on the combination of experimentation and modeling, since presynaptic terminals are not easily accessible for experimental manipulations, and all the vesicle pools cannot be measured precisely. Our overall approach is to investigate regulation of vesicle pools by synapsin, to simulate quantitatively the dynamics of vesicle pools, and to verify modeling by its ability to account for different facilitation forms and their regulation by synapsin. All the developed computational algorithms will be available to other scholars.