Mechanisms of inhibitory GABA-A and glycine receptor clustering in health and disease

中枢神经系统是一个复杂的，错综复杂的神经细胞网络，传递和接收信息。这种交流发生在被称为突触的特殊接触部位。在这些部位，到达的神经冲动导致从“突触前”细胞释放化学神经递质，然后与嵌入相邻的“突触后”神经细胞的细胞膜中的受体分子相互作用。这些受体中的一些类型，称为甘氨酸和GABA-A受体，被归类为抑制性受体，因为它们具有完整的氯离子通道。这些通道响应神经递质的开放改变了细胞的电状态，或者传递或微妙地改变传入的神经冲动。调节突触传递的机制对于理解大脑的正常和疾病状态非常重要。事实上，许多正在使用或正在开发的麻醉剂、镇静剂和抗焦虑药物主要通过GABA-A或甘氨酸受体起作用。这些药物的治疗性质为理解这些受体如何定位于突触提供了一个令人信服的理由。我们以前已经表明，与突触簇蛋白（如collybistin）相关的基因突变会导致焦虑、攻击性行为、癫痫、睡眠障碍和智力残疾。单个基因的破坏可以导致这样一系列症状的原因是collybistin的丢失导致几种突触成分的破坏和错误定位，包括称为桥蛋白的支架蛋白和某些抑制性GABA-A受体。然而，其他抑制性受体的位置不受影响，这表明突触簇的其他机制必须存在。该研究项目的目的是：i）研究GABA-A受体与桥蛋白和collybistin相互作用的分子基础; ii）确定将蛋白质转运到突触位点的称为驱动蛋白的马达蛋白是否对这种聚集过程至关重要; iii）找出另外两种突触蛋白IQSEC 2和IQSEC 3是否也有助于抑制性受体的突触聚集。我们希望，详细了解健康和疾病中突触受体聚集的潜在机制，将有助于更好地诊断和治疗患有焦虑、攻击性行为、癫痫、睡眠障碍和智力残疾的个体。我们的研究也将对研究影响其他神经递质受体突触位置的人类疾病具有重要意义。

The central nervous system is a complex, intricate network of nerve cells that transmit and receive messages. This communication occurs at specialised sites of contact known as synapses. At these sites, an arriving nerve impulse causes the release of a chemical neurotransmitter from the 'presynaptic' cell which then interacts with receptor molecules embedded in the cell membrane of a neighbouring 'postsynaptic' nerve cell. Some types of these receptors, called glycine and GABA-A receptors, are classified as inhibitory receptors because they have an integral chloride ion channel. The opening of these channels in response to the neurotransmitter alters the electrical state of the cell either transmitting or subtly altering the incoming nerve impulse. The mechanisms that regulate synaptic transmission are important in understanding normal and diseased states of the brain. Indeed, many anaesthetics, sedatives and anti-anxiety drugs in use or under development act primarily via GABA-A or glycine receptors. The therapeutic nature of these agents provides a compelling reason for understanding how these receptors are localised at synapses. We have previously shown that mutations in genes associated with synaptic clustering proteins, such as collybistin, cause anxiety, aggressive behaviour, epilepsy, sleep disturbances and intellectual disability. The reason that disruption of a single gene can cause such a range of symptoms is that loss of collybistin causes disruption and mislocalisation of several synaptic components, including a scaffolding protein known as gephyrin and certain inhibitory GABA-A receptors. However, the location of other inhibitory receptors was unaffected, suggesting that other mechanisms of synaptic clustering must exist. The aims of this research project are: i) To investigate the molecular basis of GABA-A receptor interactions with gephyrin and collybistin; ii) To establish whether motor proteins called kinesins that transport proteins to synaptic sites are crucial for this clustering process; iii) To find out if two additional synaptic proteins, IQSEC2 and IQSEC3, also contribute to the synaptic clustering of inhibitory receptors. It is our hope that a detailed understanding of the mechanisms underlying synaptic receptor clustering in health and disease will enable better diagnosis and treatment of individuals with anxiety, aggressive behaviour, epilepsy, sleep disturbances and intellectual disability. Our study will also have important implications for research into human disorders affecting the synaptic location of other neurotransmitter receptors.