Mechanisms underlying synapse-specific clustering of GABAA receptors

GABAA 受体突触特异性聚集的机制

• 批准号: G0800498/1
• 负责人: Alex Thomson
• 金额: $ 133.26万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0800498%2F1
• 关键词: Mechanisms; underlying; synapse; specific; clustering

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.

为了识别我们周围的事物、处理信息并以有用、安全和社会可接受的方式做出反应，大脑会执行极其复杂的计算。我们的大脑包含数百万个神经细胞（神经元），它们处理信息并通过突触将其传输到其他神经元。由于神经元有多种类型，因此突触也有多种不同类型。即使一种突触的细微变化也会产生行为或情绪变化，并导致神经或精神疾病。该项目的重点是抑制性突触，它会减少其他神经元的活动，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。许多药物会影响其功能，例如。麻醉剂、镇静剂和抗焦虑药物，而激素水平变化引起的某些突触变化会导致经前紧张、每月某些时候癫痫发作的易感性增加以及“产后忧郁症”。在每个突触处，一个神经元输出纤维的微小且高度专业化的区域非常靠近另一个神经元的表面，从而形成功能连接。在如此形成的突触的每一侧，蛋白质聚集成高度特异性、复杂的功能单元。这些突触蛋白是高度专业化的成分。我们了解它们的结构、它们控制信息传递时相互之间的相互作用，以及不同类型的突触使用的细微不同的组件。我们尚不了解的是如何选择它们中的每一个并将其插入到正确的位置，或者确切地说每种组件的组合如何产生一组独特的功能特性。这种精度水平的第一个要求是两个神经元（一个位于突触的两侧）能够相互识别。神经元 A 可以接收来自二十种不同类型的神经元的输入，并且可以向二十种不同类型的其他神经元生成输出。因此，它必须使用每个突触的正确组件以极高的精度构建自己的一半突触。因此，要回答的第一个问题是——它如何识别另一侧的神经元？直到最近，这种纯粹的复杂性还阻碍了更深入的理解。然而，进一步探索所需的工具正在变得可用，并且随之而来的是对支撑这种精度的机制的新见解。我们将把这些工具结合起来，采用两种并行的、新颖的、互补的实验方法来解决这个问题。