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

神经元回路本质上是大脑各方面功能的生物底物。突触是神经元的连接点，是理解这些电路的关键。它们不断地重塑，以回应新奇的经历，这可能是学习和形成长期记忆的解剖学基础。在过去的一个世纪里，突触的研究可能比任何其他细胞结构都要多，神经科学在其最广泛的意义上提供了所有的工具(从解剖学到遗传学，从生理学到生物化学，从细胞到分子生物学)。结构生物学使用多种方法来定义生物分子的形状和作用机制，包括使用X射线和电子束。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，突触间隙是将两个相连的神经元的外膜分开的空间。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水平的复杂性，即多分子组装，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。跨突触蛋白组合在(至少)两个方面很重要：它们提供结构支持，在物理上将突触前和突触后神经元联系在一起，并为这些细胞之间的交流提供途径。后一个方面的描述尤其糟糕，我的一个主要假设是，这种组装是高度动态的，大小和可能的形状都会随着神经元的活动而变化。从基础科学的角度来看，理解这种机制应该会为突触信号的实际工作提供一个全新的视角。我的工作也将在医学上产生重要影响，通过提供控制突触稳定性的分子机制的快照。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标志。伴随而来的是大脑中涉及学习、记忆和执行功能的区域的突触数量减少。此外，突触信号的故障以及突触形态和数量的变化与大多数精神和神经障碍有关，从智力低下和自闭症到阿尔茨海默氏症和成瘾。令人惊讶的是，欧洲脑理事会和欧洲神经精神药理学院最近的一份报告称，超过1.6亿欧洲人(约占27个欧盟国家人口的38%，加上瑞士、挪威和冰岛)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，目前约有75万人患有痴呆症(每14名65岁以上的人中就有一人患有痴呆症，每6名80岁以上的人中就有1人患有痴呆症)，每年给社会造成的损失超过170亿GB。随着预期寿命的增加，这些数字可能会上升。令人惊讶的是，最近的报告显示，一些中枢神经系统疾病(包括某些形式的脑炎和共济失调)可以通过免疫疗法进行治疗。这是因为它们是由抗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，旨在识别更多可以通过这种创新和相对简单的方式解决的疾病。

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.