Ultrastructure and regulation of adhesion at a genetically tractable model synapse

行为、学习、记忆和认知都是构成神经系统的复杂神经元网络的外在表现。神经网络由神经细胞组成，这些神经细胞显示出长长的突起，形成与其他神经、肌肉或腺体细胞可复制的接触点。电信号沿着这些过程传递，并传递到接触点的其他细胞。突触是在这些接触处进行信息传递的专门结构。由于突触可以在传递过程中操纵或过滤信息，因此它们是神经网络中信息流的关键调节器，对神经系统的功能和行为至关重要。突触功能不正常会导致可怕的后果，如癫痫发作、智力迟钝或死亡。在神经系统发育过程中，当突触形成时，一些结构特征必须正确地建立起来，才能适当地执行它们的功能。它们必须建立在正确的位置（即在适当细胞之间的接触处）；突触组件必须在触点的信号发送和接收侧完全相反地组装；在每个神经元接触处，突触必须以适当的数量聚集在一起，以使信息传递的强度与它在神经元网络中的位置相称。所谓的粘附分子在所有这些发育过程中起着重要作用。粘附分子位于细胞表面，并粘附在其他表面的分子或沉积在细胞周围的物质上。因此，粘附分子将细胞聚集在一起并固定在身体的某些部位。神经元和突触上的靶细胞之间的细胞间粘附也是如此。因此，许多突触粘附分子已经被描述，但它们随时间的调节以及不同种类的粘附分子之间导致正确突触发育的相互依赖性很难被理解。在这里，我们建议将突触粘附的研究重点放在遗传模式生物果蝇的神经和肌肉细胞之间众所周知的突触接触上。果蝇提供了许多优势，加速了对基因及其产物（如粘附分子）的研究。由于基因在进化过程中经常被保存下来，并且在像人类和果蝇这样遥远的物种之间是相似的，因此我们的研究将对突触相关的医学相关研究产生影响。该项目将广泛使用高度复杂的成像技术（电子显微镜），该技术可以以极高的分辨率查看细胞专业化。在这里，我们将研究粘附分子形成的详细结构，粘附分子将果蝇的神经肌肉接触结合在一起。从这些观察中，我们可以推断出参与其中的分子类型，以及它们在突触接触的不同区域之间是否不同。同时，我们将分析具有影响粘附分子的遗传疾病（突变）的果蝇突触的潜在缺陷。结合结构描述，这将帮助我们精确定位这种特殊突触接触所需的分子，并确定它们是如何排列以实现其功能的。最后，我们将尝试了解这些分子在从早期神经肌肉接触到功能性突触接触的最终外观和大小的逐步发展过程中如何发挥作用。

Behaviour, learning, memory and cognition are all outward manifestations of the complex neuronal networks that make up the nervous system. Neuronal networks are composed of nerve cells which display long projections forming reproducible points of contact with other nerve, muscle or gland cells. Electrical messages pass along these processes and are transmitted to other cells at the points of contact. Synapses are specialised structures at these contacts which carry out the information transfer. Since they can manipulate or filter information during the transfer process, synapses are key regulators of information flow in neuronal networks, essential for nervous system function and behaviour. Inappropriate function of synapses has dire consequences such as epileptic attacks, mental retardation or death. To execute their function appropriately, a number of structural features have to be correctly established when synapses form during nervous system development. They have to be established at the right places (i.e. at contacts between appropriate cells); synaptic components have to assemble precisely opposite on the signal-sending and -receiving sides of the contact; at each neuronal contact synapses have to assemble in appropriate numbers so that information transfer occurs at a strength adequate for its position in the neuronal network. So called adhesion molecules contribute essentially to all these developmental processes. Adhesion molecules sit on the surface of cells and stick to molecules on other surfaces or of material deposited in the surrounding of cells. Thus, adhesion molecules hold cells together and in certain body locations. The same is true for intercellular adhesion between neurons and their target cells at synapses. Accordingly, a number of synaptic adhesion molecules have been described, but their regulation over time and interdependencies between different classes of adhesion molecules leading to proper synapse development are hardly understood. Here we propose to focus studies of synaptic adhesion on a well known synaptic contact between nerve and muscle cells in a genetic model organism, the fruitfly Drosophila. Drosophila provides numerous advantages speeding up research into genes and their products (such as adhesion molecules). Since genes are often preserved during evolution and are similar between species as distant as humans and the fruitfly, our research will have implications for synapse-related medically relevant research. This project will make extensive use of highly sophisticated imaging techniques (electron microscopy) which allows to view cellular specialisations at extremely high resolution. Here, we will look into the detailed structures formed by adhesion molecules holding neuromuscular contacts of the fruitfly together. From such observations we can deduce, what kind of molecules are involved and whether they differ between different areas of the synaptic contact. In parallel, we will analyse potential defects of synapses in flies with inherited diseases (mutations) affecting adhesion molecules. Together with the structural descriptions, this will help us to pinpoint those molecules required at this particular synaptic contact and determine how they are arranged to carry out their function. Finally, we will try to understand how these molecules function during development in the stepwise process from the early neuromuscular contact to the final appearance and size of the functional synaptic contact.