I want to ask a stupid question that when we talk the concentration of neurotransmitters, or when we use MRS to measure the neurotransmitters, do we just measure the neurotransmitters in synaptic clefts or both the clefts and vesicles?
Take GABA as an example. When we use the MEGA-PRESS to measure the GABA concentration, what neurotransmitter are we measuring?
This is a great question, and one I have asked myself as well. There are a few things to consider. First, there’s the question, “What signal are we measuring?” If you’re using MEGA-PRESS, or any similar sequence that doesn’t have macromolecule suppression, the signal you get at 3 ppm is most accurately called “GABA+”. GABA+ consists of the signal from GABA, homocarnosine, and co-edited macromolecules. There isn’t an easy way to isolate just the signal from GABA without changing or adding to the sequence.
Second, there’s the question, “Which GABA molecules does this signal represent?” The simplest answer is that the 3 ppm peak represents ALL of the GABA within the voxel, including GABA in the extracellular space, cytosol, and vesicles. A more complicated answer would be that the 3 ppm GABA signal represents all of the MR-visible GABA at your TE (68 ms). There is the potential that GABA molecules stored in vesicles have a much shorter T2 due to being bound to macromolecules inside the vesicle. In this case, the MR signal from vesicular GABA will have most likely decayed by 68 ms. See this paper and its references for an interesting discussion and model for compartmental glutamate / GABA changes on short time scales. The above paper seems to use 30% / 70% as their vesicular / cytosolic GABA fraction at rest. Given that, one answer would be that, at rest, the vast majority of the GABA signal comes from cytosolic GABA, which is potentially ~70% of total neuronal GABA. However, I’m not sure how widely accepted this theory is within the field.
I hope that helps, and I welcome any thoughts or references from those more familiar with the topic. Thanks!
Edit: this was also partially answered here with some links to good resources.
Department of Psychiatry
University of California, Los Angeles
Thank you very much! You really gave me the answer that solved my doubts! Thank you for your patient response!