QUANTITATIVE STUDY OF PRESYNAPTIC FACILITATION

描述(由申请人提供)：突触有效性的变化是神经网络存储和检索信息的能力的基础，信息是学习和记忆的细胞水平表征。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瞬间变得更有效的现象。对易化的经典解释是，神经重复刺激增加了突触前释放部位的钙浓度，进而增加了每个部位释放囊泡的可能性。然而，最近情况变得很明显，这种解释是不完整的。我们最近已经证明，被适当激活以释放的突触小泡(可释放的小囊泡池)的数量的变化也有助于易化。我们建议定量研究突触前机制对可释放的囊泡池的调节如何影响易化。突触素是一类神经元特异性磷酸蛋白家族，它调节囊泡与肌动蛋白细丝的结合，从而控制囊泡的可获得性。与可释放囊泡池在促进过程中的作用一致，我们最近证明了递质的释放和促进是由突触素以一种依赖于钙的方式调节的。在目前的应用中，我们建议定量研究突触蛋白如何调节突触前小泡的循环，在可释放池中重新招募小泡，从而调节不同形式的促进作用。我们的建议依赖于实验和建模的结合，因为突触前终末不容易进行实验操作，并且所有的囊泡池都不能被精确测量。我们的总体方法是研究突触素对囊泡池的调节，定量模拟囊泡池的动力学，并通过其解释不同促进形式的能力以及突触素对它们的调节来验证建模。所有开发的计算算法将可供其他学者使用。

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.