NMDA Receptor Subtype-Dependent Mechanisms of Action of Memantine and Ketamine

 描述(由申请人提供)：这项建议的重点是了解两种临床相关的药物，美金刚和氯胺酮，在生理条件下如何单独作用于同一靶点。美金刚被批准用于治疗阿尔茨海默病，并在治疗其他神经退行性疾病方面显示出希望，而氯胺酮作为一种快速抗抑郁药和治疗神经病理性疼痛显示出希望。尽管患者对美金刚的耐受性很好，但氯胺酮会引起类似精神分裂症症状的副作用。美金刚和氯胺酮结合并抑制N-甲基-D-天冬氨酸受体(NMDAR)。NMDAR是一种大脑蛋白质，由神经递质谷氨酸激活，参与神经元之间的通讯。NMDAR负责学习、记忆形成和其他高级认知功能。NMDAR功能障碍与抑郁症、神经病理性疼痛、精神分裂症和包括阿尔茨海默病在内的神经退行性疾病的发展和进展有关。这项建议的总体目标是在受体和细胞水平上加深我们对美金胺和氯胺酮在生理条件下的不同作用的理解，例如在突触活动期间，在饱和或非饱和谷氨酸存在时，以及在生理浓度的镁存在下。这项建议的长期目标是更好地了解生理条件下的NMDAR拮抗作用，以便确定有益药物作用的特征，并将开放通道阻滞剂的模型纳入神经退行性疾病和神经精神疾病的电路模型。来自经修饰表达NMDAR的细胞的电生理记录将用于评估美金刚和氯胺酮对NMDAR亚型的作用。这些实验的结果将被纳入美金刚和氯胺酮抑制NMDAR的定量动力学模型。然后，我们将用小鼠脑片中神经元的电生理记录来验证我们的模型。我们的模型将有助于理解美金刚和氯胺酮对NMDAR作用的机制差异。这项提案的发现将具有广泛的翻译潜力，并加深我们对NMDAR对抗的理解。

 DESCRIPTION (provided by applicant): This proposal is focused on understanding how two clinically relevant drugs, memantine and ketamine, act individually on the same target under physiological conditions. Memantine is approved for the treatment of Alzheimer's disease and has shown promise in treatment of other neurodegenerative diseases, whereas ketamine has shown promise as a rapid antidepressant and as a treatment for neuropathic pain. Although memantine is well tolerated by patients, ketamine causes side effects that resemble the symptoms of schizophrenia. Memantine and ketamine bind to and inhibit N-methyl-D-aspartate receptors (NMDARs). NMDARs are brain proteins that are activated by the neurotransmitter glutamate and are involved in communication between neurons. NMDARs are responsible for learning, memory formation, and other higher order cognitive functions. NMDAR dysfunction is implicated in the development and progression of depression, neuropathic pain, schizophrenia, and neurodegenerative diseases, including Alzheimer's disease. The overall goal of this proposal is to further our understanding, at both the receptor and cellular level, of how memantine and ketamine actions differ under physiological conditions such as during synaptic activity, in the presence of saturating or non-saturating glutamate, and in the presence of a physiological concentration of Mg2+. The long- term goals of this proposal are to better understand NMDAR antagonism under physiological conditions in order to identify features of beneficial drug actions and to incorporate models of open channel blockers into circuit models of neurodegenerative and neuropsychiatric illnesses. Electrophysiological recordings from cells modified to express NMDARs will be used to assess memantine and ketamine action on subtypes of NMDARs. Results from these experiments will be incorporated into quantitative kinetic models of NMDAR inhibition by memantine and ketamine. We will then validate our models with electrophysiological recordings from neurons in brain slices from mice. Our models will aid in the understanding of mechanistic differences between memantine and ketamine action on NMDARs. Findings from this proposal will have broad translational potential and deepen our understanding of NMDAR antagonism.