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.

Public Health Relevance

Glutamate neurotransmission is a key process in brain function and is abnormal in many common and severe brain disorders such as epilepsy, Alzheimer's disease, and schizophrenia. This project aims to develop an in vivo magnetic resonance spectroscopy approach to quantify glutamate release from synaptic vesicles noninvasively. We will develop the technique in a rodent model but hope to apply it in future human studies and ultimately in monitoring people with brain disorders and developing new treatments for them.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Special Emphasis Panel (ZMH1)
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Nadler, Laurie S
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Mclean Hospital
United States
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Kim, Sang-Young; Chen, Wei; Ongur, Dost et al. (2018) Rapid and simultaneous measurement of phosphorus metabolite pool size ratio and reaction kinetics of enzymes in vivo. J Magn Reson Imaging 47:210-221