The structural biology of synaptic connectivity: understanding the extracellular organizers of neurotransmission

神经回路本质上是脑功能各个方面的生物基础。而突触，神经元的连接点，掌握着理解这些回路的关键。它们会不断地对新的经历做出反应，这可能是学习和形成持久记忆的解剖学基础。在过去的一个世纪里，利用神经科学提供的所有工具（从解剖学到遗传学，生理学到生物化学，细胞生物学到分子生物学），对突触的研究可能比其他任何细胞结构都要多。结构生物学采用多种方法，包括使用x射线和电子束，来定义生物分子的形状和作用机制。我的目标是应用这种技术来研究跨越所谓的“突触间隙”的特殊类型的蛋白质组合，突触间隙是分隔两个相连神经元外膜的空间。传统上，这些蛋白质是在分离、纯化和结晶后进行研究的。例如，这种方法提供了关于小分子神经递质受体的详细原子组织的丰富信息。但是，如果我们要了解突触是如何工作的，我们必须尝试达到更高的复杂性水平，即多分子组装的复杂性，原因很简单，在现实生活中，蛋白质永远不会单独工作。这是我研究的一个关键目标。跨突触蛋白组装在（至少）两个方面是重要的：它们提供结构支持，将突触前和突触后神经元物理地连接在一起，它们为这些细胞之间的通信提供途径。尤其是后一个方面，我的主要假设之一是，这种组合是高度动态的，会根据神经元活动改变大小和形状。从基础科学的角度来看，理解这种机制应该为突触信号的实际工作提供一个全新的视角。通过提供控制突触稳定性的分子机制的快照，我的工作也将对医学产生重要影响。在人类中，正常的健康衰老以不同程度的神经退化和认知障碍为特征。这些都伴随着大脑中与学习、记忆和执行功能有关的区域突触数量的减少。此外，突触信号的功能障碍以及突触形态和数量的变化与大多数精神和神经疾病有关，从智力迟钝和自闭症到阿尔茨海默病和成瘾。令人惊讶的是，欧洲大脑理事会和欧洲神经精神药理学学院最近的一份报告指出，超过1.6亿欧洲人（约占欧盟27国加上瑞士、挪威和冰岛人口的38%）患有精神障碍。例如，根据阿尔茨海默氏症协会的数据，仅在英国，目前就有大约75万人患有痴呆症（65岁以上的人中有1 / 14,80岁以上的人中有1 / 6），每年给社会造成的损失超过170亿英镑。随着预期寿命的延长，这些数字可能还会上升。令人惊讶的是，最近的报告显示，许多中枢神经系统疾病（包括某些形式的脑炎和共济失调）可以通过免疫疗法治疗。这是因为它们是由针对突触蛋白的自身抗体触发的。我的实验室将与临床免疫学家和一家专门从事高通量筛查的当地公司合作，帮助开发新的诊断工具，旨在确定更多可以通过这种创新和相对直接的方式解决的疾病。

Neuronal circuits are essentially the biological substrate for all aspects of brain function. And synapses, the connecting points for neurons, hold the key to understanding these circuits. They are continuously remodelled in response to novel experiences, and this is likely the anatomical substrate for learning and formation of long-lasting memories. Synapses have probably been studied more than any other cellular structure over the past century, with all the tools afforded by neuroscience in its broadest possible sense (from anatomy to genetics, physiology to biochemistry, cell to molecular biology). Structural biology employs a combination of methods, including the use of X-rays and electron beams, to define shapes and mechanisms of action of biological molecules. I aim to apply such techniques to study the special type of protein assemblies that span the so-called "synaptic cleft", the space that separates the outer membranes of two connected neurons. Traditionally, these proteins were studied in isolation, following purification and crystallization. This approach provided a wealth of information regarding the detailed atomic organization of receptors for small molecule neurotransmitters, for example. But if we are to understand how synapses work we must attempt to reach a higher level of complexity, that of multi-molecular assemblies, for the simple reason that in real life proteins never work alone. This is a key goal of my research. Trans-synaptic protein assemblies are important in (at least) two ways: they provide structural support, physically tying together the pre- and post- synaptic neurons, and they provide avenues for communication between these cells. This latter aspect in particular is poorly characterised, and one of my main hypotheses is that such assemblies are highly dynamic, changing size and possibly shape in response to neuronal activity. From a basic science point of view, understanding such a mechanism should provide a completely novel view into how synaptic signalling actually works. My work will also have an important impact in medicine, by providing snapshots into the molecular mechanisms that control synaptic stability. In humans, normal healthy aging is marked by variable degrees of neural deterioration and cognitive impairment. These are accompanied by a reduction in synapse numbers in regions of the brain involved in learning, memory and executive functions. Moreover, a malfunction of synaptic signalling and changes in synaptic morphology and number are linked to the majority of psychiatric and neurological disorders, from mental retardation and autism to Alzheimer's disease and addiction. Astonishingly, a recent report from the European Brain Council and the European College of Neuropsychopharmacology states that more than 160 million Europeans (~38% of the population in the 27 EU countries plus Switzerland, Norway and Iceland) suffer from mental disorders. For example, in the UK alone, according to Alzheimer's society, there are currently about 750,000 people suffering form dementia (one in 14 people over 65 years of age, and one in six over 80), costing the society in excess of £17 billion a year. These numbers are likely to go up as life expectancy increases. Surprisingly, recent reports revealed that a number of central nervous system disorders (including certain forms of encephalitis and ataxia) can be treated by immunotherapy. This is because they are triggered by autoantibodies against synaptic proteins. Working together with clinical immunologists and a local company specialized in high-throughput screening, my laboratory will help develop new tools for diagnosis, aiming to identify more conditions that can be tackled in this innovative and relatively straightforward way.