NMDA modulation of diabetes-induced glutamate synaptic plasticity

描述（由申请人提供）：糖尿病是一个主要的健康问题，影响美国近2600万人。糖尿病引起的严重并发症包括心脏病、中风、高血压、失明、神经系统损伤和自主神经功能障碍。开发成功的糖尿病治疗（与治疗症状相比）的一个主要障碍是关于有助于控制代谢稳态的多方面和冗余系统的相对知识差距。这项建议调查疾病相关的可塑性中枢神经回路参与自主控制，包括控制血糖稳态。实验利用1型糖尿病的模型，但研究结果将更广泛地适用于其他形式的糖尿病，因为自主神经功能障碍会增加患2型糖尿病的风险。迷走神经背侧复合体的前自主神经元（Preautonomic neurons）是葡萄糖感受器，也对葡萄糖稳态的自主调节有重要作用，其中包括孤束核（NTS）中的二级内脏感觉神经元和迷走神经背侧运动核（DMV）中的节前副交感运动神经元。迷走神经运动输出在糖尿病中被抑制，导致自主神经失调，包括过量的肝葡萄糖产生和胃动力障碍。初步结果表明，DMV中的谷氨酸释放在1型糖尿病模型中持续增强，其方式与对长时间高血糖的可能代偿反应的发展一致，这表明稳态可塑性减轻了糖尿病中观察到的迷走神经输出减少。此外，与对照组相比，NMDA受体调节对糖尿病小鼠中谷氨酸释放具有相对较大的影响。这个探索性的建议旨在确定最近发现的糖尿病诱导的DMV神经元紧张性兴奋驱动增强的原因和基本特征。来自对照和糖尿病小鼠切片中迷走复合神经元的电生理记录将用于获得与链脲佐菌素处理的小鼠（1型糖尿病模型）中糖尿病发展相关的NMDA受体敏感性变化相关的功能细胞数据。目的1将确定是否最近确定的NMDA受体位于突触前末梢接触DMV细胞上调糖尿病。目的2将确定是否突触后NMDA受体上的体细胞的一部分，已确定的NMDA能NTS神经元的项目DMV上调糖尿病。还将确定这些变化对葡萄糖和胰岛素的敏感性。结果将指导未来的研究，旨在从系统的角度，基于调节脑干中的特定神经功能，最终解决患者糖尿病相关的自主神经失调的疾病修饰疗法。

DESCRIPTION (provided by applicant): Diabetes mellitus is a major health concern, affecting nearly 26 million people in the United States. Serious complications result from diabetes including heart disease, stroke, hypertension, blindness, nervous system damage, and autonomic dysfunction. A major impediment to developing successful diabetes treatments (versus treating symptoms) is the relative knowledge gap regarding the multifaceted and redundant systems that contribute to control of metabolic homeostasis. This proposal investigates disease-related plasticity of central neural circuitry involved in autonomic control, including control of blood glucose homeostasis. Experiments utilize a model of type 1 diabetes, but findings will more broadly apply to other forms of diabetes, since autonomic dysfunction increases the risk of developing type 2 diabetes. Preautonomic neurons of the dorsal vagal complex, which contains second-order viscerosensory neurons in the nucleus tractus solitarius (NTS) and preganglionic parasympathetic motor neurons in the dorsal motor nucleus of the vagus (DMV), are glucosensors and also contribute significantly to autonomic regulation of glucose homeostasis. Vagal motor output is suppressed in diabetes, leading to autonomic dysregulation, including excess hepatic glucose production and gastric motility dysfunction. Preliminary results show that glutamate release in the DMV is persistently enhanced in a model of type 1 diabetes, in a manner consistent with development of a possible compensatory response to prolonged hyperglycemia that suggests homeostatic plasticity that mitigates against the decreased vagal output seen in diabetes. In addition, NMDA receptor modulation has a relatively larger effect on glutamate release in diabetic mice versus controls. This exploratory proposal aims to determine the causes and underlying features of the recently-discovered, diabetes-induced enhancement of tonic excitatory drive to DMV neurons. Electrophysiological recordings from vagal complex neurons in slices from control and diabetic mice will be used to obtain functional cellular data related to NMDA receptor sensitivity changes associated with diabetes development in the streptozotocin-treated mouse, a model of type 1 diabetes. Aim 1 will determine if recently-identified NMDA receptors located on presynaptic terminals contacting DMV cells are upregulated in diabetes. Aim 2 will determine if postsynaptic NMDA receptors on the somadendritic portion of identified glutamatergic NTS neurons that project to the DMV are upregulated in diabetes. The sensitivity of these changes to glucose and insulin will also be identified. Results will guide future studies aimed at disease-modifying therapies from a systemic standpoint, based on modulating specific neural functions in the brainstem to eventually address diabetes-related autonomic dysregulation in patients.