Mechanisms underlying synapse-specific clustering of GABAA receptors

为了识别我们周围的事物，处理信息，并以一种有用、安全和社会接受的方式做出反应，大脑进行极其复杂的计算。我们的大脑包含数以百万计的神经细胞(神经元)，它们处理信息并通过突触将信息传递给其他神经元。因为有许多类型的神经元，所以也有许多不同类型的突触。即使是一种类型的突触的微小变化也会导致行为或情感上的变化，并导致神经或精神疾病。这个项目的重点是抑制突触，这种突触会降低其他神经元的活动，阻止它们对其他输入的反应。他们精确地选择要处理的信息，并控制不适当的感知、反应和行为模式。许多药物会影响它们的功能，例如。麻醉剂、镇静剂和抗焦虑药物，而这些突触中的一些由激素水平变化引起的变化会导致经前紧张，在一个月的某些时间增加癫痫发作的易感性，并导致产后抑郁。在每个突触，一个神经元的输出纤维的一个微小的、高度专门化的区域非常接近另一个神经元的表面，形成功能连接。在这样形成的突触的两侧，蛋白质聚集成高度特异的复杂功能单位。这些突触蛋白是高度专门化的成分。我们知道它们的结构，它们在控制信息传递时彼此之间的相互作用，以及不同类型的突触使用的微妙不同的组件。我们还不明白的是，它们中的每一个是如何被选择并插入到正确的位置，或者确切地说，每个组件的组合如何导致一组独特的功能特性。达到这种精确度的第一个要求是两个神经元，一个在突触的两边，相互识别。神经元A可能接受来自20个不同类型神经元的输入，并可能向20个不同类型的其他神经元产生输出。因此，它必须使用每个突触上的正确组件，以极高的精度构建每个突触的自己的一半。因此，要回答的第一个问题是--它如何识别另一边的神经元？直到最近，纯粹的复杂性还阻碍了对这一问题的更深入理解。然而，进一步探测所需的工具正在变得可用，并随之而来的是对支撑这种精确度的机制的新见解。我们将把这些工具结合成两种平行的、新颖的和互补的实验方法来解决这个问题。

To recognise things around us, process information and respond in a useful, safe and socially acceptable way, the brain performs extremely complex computations. Our brains contain millions of nerve cells (neurones) which process information and transfer it to other neurones via synapses. Since there are many types of neurones, there are many different types of synapse. Even subtle changes at one type of synapse can produce behavioural, or emotional changes and contribute to neurological or psychiatric disease. This project focusses on inhibitory synapses which reduce activity in other neurones, blocking their responses to other inputs. They select precisely which information is processed and control inappropriate perceptions, responses and behaviour patterns. Many drugs affect their function, eg. anaesthetics, sedatives and anti-anxiety drugs, while changes at some of these synapses caused by changing hormone levels contribute to premenstrual tension, increased epileptic seizure susceptibility at some times of the month and to ?postpartum blues?. At each synapse, a minute, highly specialised region of the output fibre of one neurone comes very close to the surface of another making a functional connection. On each side of the synapse so formed, proteins cluster into highly specific, complex functional units. These synaptic proteins are highly specialised components. We know something of their structures, their interactions with each other as they control information transfer and that subtly different components are used by different types of synapse. What we do not yet understand is how each of them is selected and inserted at just the right place, or precisely how each combination of components leads to one set of distinctive functional properties. A first requirement for this level of precision is for two neurones, one on either side of the synapse, to recognise each other. Neurone A might receive inputs from twenty different types of neurones and might generate output onto twenty different types of other neurones. It must therefore construct its own half of each of these synapses with enormous precision using just the right components at each one. The first question to be answered is therefore - how does it recognise the neurone on the other side ? The sheer complexity has, until recently, precluded a deeper understanding. The tools needed to probe further are however, becoming available and with them, new insight into the mechanisms that underlie this precision. We will combine these tools in two parallel, novel and complementary experimental approaches to the problem.