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讯。nmda亚型受体的激活介导了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。谷氨酸激活的不同亚型NMDARs的功能和药理学是由其亚基组成决定的；这个四聚体离子通道需要两个glun1型亚基和两个glun2型亚基。关于glun2型亚基（如GluN2A或GluN2B）的发育和疾病调控的信息非常丰富（Paoletti等人2013年进行了综述），但对于GluN1-NMDAR亚基的亚型调控知之甚少。GluN1剪切成两种主要类型（GluN1-a和GluN1-b）决定了NMDA受体的功能和药理特性。最近有研究表明，以小鼠为实验模型，海马中GluN1亚基的同一性可以调节突触可塑性和记忆。GluN1-a与增强的可塑性（Sengar et al, 2019）和潜在的增强的兴奋毒性有关。因此，GluN1-a或GluN1-b的丰度或突触定位是否受到衰老或疾病的影响具有重要意义，但目前尚不清楚。我们最近证实，这两种类型的GluN1都在人脑样本中表达（未发表）。在本项目中，您将使用分子和电生理方法（如qPCR，贴片钳，Western blotting）检测GluN1在阿尔茨海默病小鼠模型和脑卒中体外模型中的丰度和调控。为了增加您的发现的影响，您将使用冷冻样本分析人类大脑，以研究Glu1N亚型的衰老和疾病调节。分析GluN1亚基在健康、衰老和疾病中的调控作用，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发现。

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 We have recently confirmed that both types of GluN1 are expressed in human brain samples (unpublished).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.