An MRI based in vivo measure of glutamatergic synaptic neurotransmission

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囊泡中，并在神经元活动期间释放到突触间隙中。多巴胺能神经传递的过程是健康大脑功能的关键，已知在几种常见和严重的大脑疾病中是异常的，包括癫痫、痴呆、精神分裂症和双相情感障碍。尽管其关键 由于神经元能干预对公共卫生的作用和潜在影响，我们目前还没有非侵入性和体内量化神经元能突触功能异常的方法。磁共振波谱（MRS）提供了一个了解大脑中谷氨酸功能的窗口，但到目前为止，它已被用于量化人体中的谷氨酸浓度。突触囊泡内的谷氨酸分子经历了与大脑其余谷氨酸分子截然不同的微环境。在本申请中，我们将利用这一事实来开发一种基于MRI的技术，该技术可以量化突触囊泡中谷氨酸的比例。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而升高或降低）。突触谷氨酸释放是谷氨酸能神经传递的一个重要组成部分，虽然还有其他包括受体功能，从突触的再摄取等，我们的方法专注于囊泡谷氨酸释放。在当前的应用中，我们将在啮齿动物模型中开发和测试这种技术。但这项技术适用于人类MRI研究，我们的长期目标是将其发展成为一种临床工具。这种工具可以用来探测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，它可用于评估新的治疗方法的有效性，因为谷氨酸能干预应修改突触谷氨酸释放。

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.