An MRI based in vivo measure of glutamatergic synaptic neurotransmission

基于 MRI 的谷氨酸突触神经传递体内测量

基本信息

批准号：
8925157
负责人：
Dost Ongur
金额：
$ 31.6万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-15 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8925157
关键词：
Address Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Anesthesia procedures Animal Model Animals Biochemical Bipolar Disorder Brain Brain Diseases Brain imaging Brain region Characteristics Chronic Clinical Clinical Research Complex Coupling Data Data Analyses Dementia Detection Diagnosis Diagnostic Diffusion Diffusion Magnetic Resonance Imaging Disease Progression Effectiveness Epilepsy Functional disorder Future Glutamates Goals Health Human Institutes Intervention Light Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Maps Measures Mental disorders Metabolic Methods Modeling Monitor National Institute of Drug Abuse National Institute of Mental Health National Institute of Neurological Disorders and Stroke Neuraxis Neurobiology Neurons Neurosciences Neurotransmitters Patient Monitoring Patients Process Process Measure Property Propofol Proteins Psychiatrist Public Health Rattus Relaxation Research Rest Rodent Model Role Schizophrenia Signal Transduction Synapses Synaptic Cleft Synaptic Vesicles Techniques Testing Therapeutic Time United States National Institutes of Health Validation Vesicle Work acute stroke arm base brain research data acquisition diffusion weighted experience glutamatergic signaling gray matter improved in vivo macromolecule nervous system disorder neurotransmission novel novel therapeutic intervention presynaptic neurons prognostic programs receptor function response reuptake synaptic function therapy development tool translational study treatment response white matter white matter change

项目摘要

DESCRIPTION (provided by applicant): Glutamate is the primary neurotransmitter in the brain. It is packaged into synaptic vesicles in the presynaptic neuron and released into the synaptic cleft during neuronal activity. The process of glutamatergic neurotransmission is key for healthy brain function and it is known to be abnormal in several common and severe brain disorders, including epilepsy, dementias, schizophrenia, and bipolar disorder. Despite its critical role and the potential impact of glutamatergic interventions on public health, we do not currently have means of quantifying abnormalities in glutamatergic synaptic function noninvasively and in vivo. Magnetic resonance spectroscopy (MRS) offers a window into glutamate function in the brain but thus far it has been used to quantify glutamate concentrations in humans. The glutamate molecules inside synaptic vesicles experience a dramatically different microenvironment than the rest of brain glutamate. In this application, we will take advantage of this fact to develop an MRI-based technique which can quantify the proportion of glutamate in synaptic vesicles. This approach will ultimately allow us to measure the process of synaptic glutamate release (as the vesicular glutamate proportion is elevated or reduced based on brain activity). Synaptic glutamate release is a critical component of glutamatergic neurotransmission, although there are others including receptor function, reuptake from the synapse etc. Our approach focuses specifically on vesicular glutamate release. In the current application, we will develop and test this technique in a rodent model. But the technique is applicable in human MRI studies and our long term goal is to develop it into a clinical tool. Such a tool could be used to probe the pathophysiology of common brain disorders and monitor patient response to therapy. In addition, it could be used to evaluate the effectiveness of new therapeutic approaches since glutamatergic interventions should modify synaptic glutamate release.

描述（由申请人提供）：谷氨酸是大脑中的主要神经递质。它被包装到突触前神经元的突触小泡中，并在神经元活动期间释放到突触间隙中。谷氨酸能神经传递过程对于健康的大脑功能至关重要，并且已知在几种常见和严重的大脑疾病中存在异常，包括癫痫、痴呆、精神分裂症和双相情感障碍。尽管它很关键为了了解谷氨酸能干预措施对公共卫生的作用和潜在影响，我们目前没有方法在体内无创地量化谷氨酸能突触功能的异常。磁共振波谱（MRS）为了解大脑中谷氨酸的功能提供了一个窗口，但迄今为止它已被用于量化人类的谷氨酸浓度。突触小泡内的谷氨酸分子经历的微环境与大脑谷氨酸的其余部分截然不同。在此应用中，我们将利用这一事实开发一种基于 MRI 的技术，该技术可以量化突触小泡中谷氨酸的比例。这种方法最终将使我们能够测量突触谷氨酸释放的过程（因为囊泡谷氨酸比例根据大脑活动升高或降低）。突触谷氨酸释放是谷氨酸能神经传递的关键组成部分，尽管还有其他包括受体功能、突触再摄取等。我们的方法特别关注囊泡谷氨酸释放。在当前的应用中，我们将在啮齿动物模型中开发和测试这项技术。但该技术适用于人体 MRI 研究，我们的长期目标是将其开发为临床工具。这种工具可用于探索常见脑部疾病的病理生理学并监测患者对治疗的反应。此外，它还可用于评估新治疗方法的有效性，因为谷氨酸能干预应该改变突触谷氨酸的释放。