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，影响着美国近2600万人。糖尿病会导致严重的并发症，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）的主要障碍是对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。本研究探讨了参与自主神经控制的中枢神经回路的疾病相关可塑性，包括血糖稳态的控制。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。迷走背神经复合体的前自主神经元是糖传感器，在葡萄糖稳态的自主调节中起重要作用，其中包括孤束核（NTS）的二级脏器感觉神经元和迷走背运动核（DMV）的神经节前副交感运动神经元。迷走神经运动输出在糖尿病中受到抑制，导致自主神经失调，包括肝糖产生过量和胃运动功能障碍。初步结果表明，在1型糖尿病模型中，DMV中的谷氨酸释放持续增强，其方式与长期高血糖可能的代偿反应的发展一致，这表明稳态可塑性减轻了糖尿病中出现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谷氨酸释放的影响相对较大。这一探索性提议旨在确定最近发现的糖尿病诱导的DMV神经元的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的迷走神经复合体神经元切片的电生理记录将用于获得与链脲佐菌素治疗小鼠（1型糖尿病模型）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与DMV细胞接触的突触前末端的NMDA受体是否在糖尿病中上调。目的2将确定投射到DMV的谷氨酸能NTS神经元的体突部分的突触后NMDA受体是否在糖尿病中上调。这些变化对葡萄糖和胰岛素的敏感性也将被确定。结果将指导未来的研究，从系统的角度出发，基于调节脑干中的特定神经功能，最终解决糖尿病患者相关的自主神经失调。

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.