Multivesicular synaptic release

描述(申请人提供)：中枢神经系统中信息的细胞间传输被认为发生在独立于相邻突触的单个突触上。然而，递质溢出和突触之间的共用等现象表明，神经元之间的点对点突触通信并不是中枢神经系统中信息传递的唯一方式。是否发生递质溢出和汇聚取决于几个变量，包括每个突触和每个突触前动作电位释放的递质数量。如果清除机制被释放压倒，递质就会从突触扩散开来。在某些突触，增加囊泡释放概率的操作会导致单个突触跟随单个突触前动作电位释放多个囊泡。这种巨大的传播量可能会压倒当地的传输者，并导致溢出。然而，在其他突触中，无论释放的概率如何，都没有发现多个囊泡的释放，这表明存在一种机制来阻止不止一个囊泡的释放。递质溢出和汇聚至少部分负责激活突触外受体，包括代谢性受体，而代谢性受体又是几种类型的短期和长期可塑性所必需的。这项提议的主要目的是确定可塑性在多大程度上依赖于递质溢出，以及溢出在多个囊泡释放中的程度。这将使用电生理和光学技术的组合来完成，研究三种不同的突触，每个突触都有不同的特征。我们的计划是利用每个突触的属性来探索，第一，多囊释放的共性，第二，其后果的多样性。中枢神经系统的所有功能，包括感觉处理、运动行为、意识和记忆，都依赖于完整的突触传递。对传播的基本分子和细胞属性的了解是在病理状态下制定合理干预措施所必需的。

DESCRIPTION (provided by applicant): Cell-to-cell transmission of information in the CNS is thought to occur at individual synapses, isolated from their neighbors. However, phenomena such as transmitter spillover and pooling between synapses have suggested that point-to-point synaptic communication between neurons is not the only method of information transfer in the CNS. Whether spillover and pooling of transmitter occurs depends on several variables including the amount of transmitter released per synapse per presynaptic action potential. If clearance mechanisms are overwhelm by release, transmitter will spread away from synapses. At some synapses, manipulations that increase the probability of vesicular release result in the release of multiple vesicles from individual synapses following single presynaptic action potentials. This large bolus of transmitter can overwhelm local transporters and result in spillover. At other synapses, however, multivesicular release has not been found regardless of the release probability suggesting that there is a mechanism that prevents release of more than a single vesicle. Transmitter spillover and pooling are at least in part responsible for activation of extrasynaptic receptors including metabotropic receptors which in turn are required for several types of short and long term plasticity. The main objectives of this proposal are to determine the extent to which plasticity depends on transmitter spillover and the degree to which spillover depends on multivesicular release. This will be accomplished using a combination of electrophysiological and optical techniques in the study of three different synapses each with distinct characteristics. The plan is to use the attributes of each of these synapses to probe, first, the generality of multivesicular release and, second, the multiplicity of its consequences. All CNS functions including sensory processing, motor behavior, consciousness, and memory depend on intact synaptic transmission. Knowledge of the fundamental molecular and cellular properties of transmission is required for the development of rational interventions in pathological states.