NMDA modulation of diabetes-induced glutamate synaptic plasticity

描述(申请人提供)：糖尿病是一个主要的健康问题，在美国有近2600万人受到影响。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方法(相对于治疗症状)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。这项建议调查了参与自主神经控制的中枢神经回路与疾病相关的可塑性，包括控制血糖的动态平衡。实验利用了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自主前神经元包括孤束核(NTS)的二级内脏感觉神经元和迷走神经背侧运动核(DMV)的节前副交感运动神经元，它们是葡萄糖感受器，对血糖稳态的自主调节也有重要作用。糖尿病患者迷走神经运动输出受到抑制，导致自主神经失调，包括肝脏葡萄糖分泌过多和胃动力障碍。初步结果显示，在1型糖尿病模型中，DMV中谷氨酸的释放持续增加，这与对长期高血糖可能产生的代偿反应相一致，这表明动态平衡可塑性可以缓解糖尿病患者迷走神经输出的减少。此外，与对照组相比，NMDA受体调节对糖尿病小鼠谷氨酸释放的影响相对更大。这一探索性建议旨在确定最近发现的糖尿病引起的DMV神经元紧张性兴奋驱动增强的原因和潜在特征。来自对照组和糖尿病小鼠切片的迷走神经复合体神经元的电生理记录将被用于获得与链脲佐菌素治疗的1型糖尿病模型小鼠的糖尿病发展相关的NMDA受体敏感性变化相关的功能细胞数据。目的1将确定最近发现的位于接触DMV细胞的突触前终末的NMDA受体在糖尿病中是否上调。目的2将确定在糖尿病中投射到DMV的已识别的谷氨酸能NTS神经元的躯体树突部分上的突触后NMDA受体是否上调。这些变化对葡萄糖和胰岛素的敏感性也将被识别出来。这些结果将指导未来的研究，旨在从系统的角度出发，基于调节脑干中特定的神经功能，最终解决患者与糖尿病相关的自主神经调节障碍，从而改善疾病治疗。

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.