Diversity and regulation of GluN1-NMDA receptor subunits in health and disease.

人类大脑中的所有思维、学习和记忆过程都需要由神经递质谷氨酸及其受体介导的突触通信。NMDA亚型受体的激活介导神经元可塑性和记忆所必需的长期分子机制。但它们的过度激活会导致神经元死亡。谷氨酸激活的NMDAR的不同亚型的功能和药理学由其亚基组成决定;这种四聚体离子通道需要两个GluN 1型亚基和两个GluN 2型亚基。关于GluN 2型亚基（例如GluN 2A或GluN 2B）的发育和疾病调控存在丰富的信息（Paoletti et al 2013综述），但对GluN 1-NMDAR亚基的亚型调控知之甚少。GluN 1选择性剪接成两种主要类型（GluN 1-a和GluN 1-B）决定NMDA受体的功能和药理学性质。最近已经表明，在海马中的GluN 1亚基的身份可以调节突触可塑性和记忆使用小鼠作为实验模型。GluN 1-a与增强的可塑性（Sengar et al 2019）和潜在增强的兴奋性毒性相关。因此，GluN 1-a或GluN 1-B丰度或突触定位是否受衰老或疾病影响具有重要意义，但目前尚不清楚。我们最近证实，这两种类型的GluN 1在人脑样本中表达（未发表）。在这个项目中，您将使用分子和电生理学方法（例如qPCR，膜片钳，蛋白质印迹）来测试阿尔茨海默病小鼠模型和中风体外模型中GluN 1的丰度和调节。为了增加您的研究结果的影响，您将使用冷冻样本分析人脑，以研究Glu 1 N亚型的衰老和疾病调节。GluN 1亚基在健康，衰老和疾病中的调节分析将有助于理解健康衰老和神经退行性疾病，并可能导致新的药物靶点的鉴定。

All thinking, learning and memory processes in the human brain require synaptic communication mediated by the neurotransmitter glutamate and its receptors. Activation of NMDA-subtype receptors mediates long-term molecular mechanisms that are essential for neuronal plasticity and memory. But their excessive activation can lead to neuronal death. The function and pharmacology of different subtypes of glutamate-activated NMDARs is determined by their subunit composition; this tetrameric ion channel requires two GluN1-type subunits, and two GluN2-type subunits. A wealth of information exists on the developmental and disease regulation of GluN2-type subunits (e.g. GluN2A or GluN2B) (reviewed by Paoletti et al 2013) however, little is known of subtype regulation of the GluN1-NMDAR subunits. Alternative splicing of GluN1 into two major types (GluN1-a and GluN1-b) determines functional and pharmacological properties of NMDA receptors. It has recently been shown that the identity of GluN1 subunits in the hippocampus can modulate synaptic plasticity and memory using mice as experimental models. GluN1-a is associated with enhanced plasticity (Sengar et al 2019) and potentially enhanced excitotoxicity. Thus, whether GluN1-a or GluN1-b abundance or synaptic localisation is affected by aging or disease is of great significance, but it is currently unknown. We have recently confirmed that both types of GluN1 are expressed in human brain samples (unpublished). In this project you would use molecular and electrophysiological methods (e.g. qPCR, patch clamp, Western blotting) to test the abundance and regulation of GluN1 in a mouse model of Alzheimer's disease and an in vitro model of stroke. To increase the impact of your findings, you will analyse human brain using frozen samples to study aging and disease regulation of Glu1N isoforms. This analysis of GluN1 subunit regulation in health, aging and disease will contribute to understanding of healthy aging and neurodegeneration and may result in the identification of new drug targets.