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递给其他神经元。由于神经元的种类很多，所以突触也有很多不同的类型。即使是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。这个项目的重点是抑制性突触，它减少了其他神经元的活动，阻止了它们对其他输入的反应。它们精确地选择处理哪些信息，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，而在这些突触的一些变化所造成的激素水平的变化有助于经前紧张，增加癫痫发作的易感性在某些时候的一个月，并？产后忧郁？在每个突触上，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，从而形成功能性连接。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，它们之间的相互作用，因为它们控制信息传递，以及不同类型的突触使用微妙的不同组件。我们还不明白的是，它们中的每一个是如何被选择并插入正确的位置的，或者说，每一种成分的组合是如何导致一组独特的功能特性的。这种精确度的第一个要求是两个神经元，一个在突触的两侧，相互识别。神经元A可能从20种不同类型的神经元接收输入，并可能向20种不同类型的其他神经元产生输出。因此，它必须在每一个突触上使用正确的组件，以极高的精度构建每一个突触中属于自己的那一半。因此，第一个需要回答的问题是--它如何识别另一侧的神经元？直到最近，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，并且随着它们的出现，对这种精确性背后的机制有了新的见解。我们将联合收割机这些工具在两个平行的，新颖的和互补的实验方法的问题。