NMDA modulation of diabetes-induced glutamate synaptic plasticity

  • Smith, Bret (PI)

Grants and Contracts Details


Diabetes mellitus is a major health concern, affecting nearly 26 million people in the United States. Serious complications resulting from diabetes including include heart disease, stroke, hypertension, blindness, nervous system damage, and digestive 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 and disorders affecting glucose metabolism. 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 based on modulating specific neural functions in the brainstem.
Effective start/end date4/10/143/31/17


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