Journal Article

A mean-field model of glutamate and GABA synaptic dynamics for functional MRS

El-Deredy, Wael, Trujillo-Barreto, Nelson J., Lea-Carnall, Caroline A., Stagg, Charlotte J., Williams, Stephen R.

2023

Overview

•The recent development of functional 1H-Magnetic resonance spectroscopy (fMRS) has allowed us to study neurotransmitter activity in vivo for the first time in humans. However, the physiological basis of the observed fMRS signal is unclear.•It has been proposed that fMRS detects shifts in metabolite concentrations as they move from presynaptic vesicles, where they are largely invisible to MRS, to extracellular and cytosolic pools, where they are visible to MRS.•We test this hypothesis using a mean field model which links the neural dynamics of neurotransmitters at the microscopic-level to the macroscopic-level imaging measurements obtained in experimental studies.•We account for the dynamics of the neurotransmitters glutamate and GABA as they cycle through the stages of exocytosis, reuptake, recycling, and repackaging into vesicles. By disregarding the contribution from the vesicular pool, our model can generate activitydependent changes in the fMRS signal in response to stimulation which are consistent with experimental findings in the literature at short timescales.•We provide a mechanistic account for the activity-dependent change in observed neurotransmitter concentrations using fMRS for a range of stimulus types. Advances in functional magnetic resonance spectroscopy (fMRS) have enabled the quantification of activity-dependent changes in neurotransmitter concentrations in vivo. However, the physiological basis of the large changes in GABA and glutamate observed by fMRS (>10%) over short time scales of less than a minute remain unclear as such changes cannot be accounted for by known synthesis or degradation metabolic pathways. Instead, it has been hypothesized that fMRS detects shifts in neurotransmitter concentrations as they cycle from presynaptic vesicles, where they are largely invisible, to extracellular and cytosolic pools, where they are detectable. The present paper uses a computational modelling approach to demonstrate the viability of this hypothesis. A new mean-field model of the neural mechanisms generating the fMRS signal in a cortical voxel is derived. The proposed macroscopic mean-field model is based on a microscopic description of the neurotransmitter dynamics at the level of the synapse. Specifically, GABA and glutamate are assumed to cycle between three metabolic pools: packaged in the vesicles; active in the synaptic cleft; and undergoing recycling and repackaging in the astrocytic or neuronal cytosol. Computational simulations from the model are used to generate predicted changes in GABA and glutamate concentrations in response to different types of stimuli including pain, vision, and electric current stimulation. The predicted changes in the extracellular and cytosolic pools corresponded to those reported in empirical fMRS data. Furthermore, the model predicts a selective control mechanism of the GABA/glutamate relationship, whereby inhibitory stimulation reduces both neurotransmitters, whereas excitatory stimulation increases glutamate and decreases GABA. The proposed model bridges between neural dynamics and fMRS and provides a mechanistic account for the activity-dependent changes in the glutamate and GABA fMRS signals. Lastly, these results indicate that echo-time may be an important timing parameter that can be leveraged to maximise fMRS experimental outcomes.

• Publisher: Elsevier Inc,Elsevier Limited,Elsevier
• Subject: Approximation / Computational neuroscience / Cytosol / FMRS / GABA / gamma-Aminobutyric Acid - metabolism / Glutamate / Glutamic Acid - metabolism / Humans / Magnetic Resonance Spectroscopy / Mathematical modelling / Mean field model / Metabolic pathways / Metabolism / Metabolites / Neurons - metabolism / Neurotransmitter Agents - metabolism / Neurotransmitters / Physiology / Schizophrenia / Synapses / Synaptic cleft / Synaptic vesicles / γ-Aminobutyric acid