The role of NMDA receptor dysfunction in epileptic disorders

中枢神经系统是一个复杂的神经细胞网络，负责传递和接收信息。这种交流主要发生在神经元表面被称为突触的特殊接触部位，但通常发生在被称为树突的精细神经元过程上。在这些部位，到达的神经冲动导致“突触前”细胞释放出一种化学神经递质，然后与邻近“突触后”神经细胞细胞膜上的蛋白质受体分子相互作用。我们的目的是研究由谷氨酸和甘氨酸两种神经递质激活的受体，这两种神经递质被归类为兴奋性NMDA受体，基于对人工毒素n -甲基- d -天冬氨酸的选择性。NMDA通过使离子通过一个完整的离子通道流动来增强神经细胞的兴奋性。这些受体的打开改变了细胞的电状态，传递或微妙地改变了传入的神经冲动。NMDA受体对突触和学习记忆过程的正常功能至关重要。NMDA受体的功能障碍与神经变性、疼痛、中风和精神分裂症有关。靶向NMDA受体的药物在阿尔茨海默病、帕金森病、疼痛和抑郁症等适应症中也显示出临床前景。最近由申请人和世界各地其他研究人员参与的研究表明，编码NMDA受体亚基的基因的遗传缺陷导致不同类型的儿童癫痫、智力残疾、自闭症和精神分裂症。初步结果表明，在这些儿童中发现的一些基因变化似乎通过NMDA受体引起过度兴奋。我们的项目旨在了解NMDA受体基因的这种变化如何导致如此广泛的神经系统疾病。我们的目标是纠正这一知识上的差距，并探索基于靶向NMDA受体的药物减少兴奋的新的潜在治疗方法。本研究项目的目的是：(i)利用生化、结构生物学和生理学方法将NMDA受体突变分类为功能丧失或功能获得，并揭示不同突变如何影响NMDA受体的基本功能；（ii）通过测试阻断NMDA受体活性的药物在恢复缺陷NMDA受体正常功能方面的有效性，探索新的治疗途径；iii)通过将NMDA受体突变引入小鼠基因组来创建新的癫痫模型。我们希望对NMDA受体功能障碍的机制、信号通路和药理学的详细了解将有助于深入了解NMDA受体在健康和疾病中的作用。

The central nervous system is an intricate network of nerve cells that transmit and receive messages. This communication occurs mostly at specialised sites of contact known as synapses found all over the surface of neurons, but typically on fine neuronal processes known as dendrites. At these sites, an arriving nerve impulse causes the release of a chemical neurotransmitter from the 'presynaptic' cell, which then interacts with protein receptor molecules in the cell membrane of a neighbouring 'postsynaptic' nerve cell. We aim to study receptors activated by two neurotransmitters, glutamate and glycine, which are classified as excitatory NMDA receptors, based on selectivity for an artificial toxin N-methyl-D-aspartate. NMDA enhances nerve cell excitability by enabling a flow of ions via an integral ion channel. The opening of these receptors alters the electrical state of the cell, either transmitting or subtly altering incoming nerve impulses. NMDA receptors are important for normal function of synapses and processes involved in learning and memory. Dysfunction of NMDA receptors has previously been implicated in neurodegeneration, pain, stroke and schizophrenia. Drugs targeting NMDA receptors have also shown clinical promise in indications such as Alzheimer's disease, Parkinson's disease, pain and depression. Recent studies involving the applicants and other researchers world-wide have shown that genetic defects in genes encoding NMDA receptor subunits cause different types of childhood epilepsy, intellectual disability, autism and schizophrenia. Initial results suggest that several of the genetic changes identified in these children appear to cause over-excitation via NMDA receptors. Our project aims to understand how such changes in NMDA receptor genes can cause such a wide range of neurological disorders. We aim to rectify this gap in knowledge, and explore new potential treatments based on targeting NMDA receptors with drugs that reduce excitation. The aims of this research project are: (i) To use biochemical, structural biology and physiological methods to classify NMDA receptor mutations as loss- or gain-of-function and to uncover how different mutations affect the basic functions of the NMDA receptor; (ii) To explore novel therapeutic routes by testing drugs that block NMDA receptor activity for their effectiveness in restoring normal function in defective NMDA receptors; iii) To create new models of epilepsy by introducing NMDA receptor mutations into the mouse genome. It is our hope that a detailed understanding of the mechanisms underlying NMDA receptor dysfunction, signalling pathways and pharmacology will enable insights into the roles of NMDA receptors in health and disease.