Neuroblox

Documentation

Back to Simulation

Neurotransmitter Cycling Model Diagram

Model Scheme

The diagram shows the reaction network including transport, utilization, and cycling of neurotransmitters between excitatory neurons, inhibitory neurons, and astrocytes.

equations

What is this model for?

This model simulates brain neurotransmitter levels in the brain, focusing on glutamate and gamma-aminobutyric acid (GABA). Use this tool to test how specific conditions or interventions affect metabolic and vesicular Glu/GABA levels.

Mechanism

MRS and traditional neurochemical studies have demonstrated a linear relationship between the synthesis rates of the neurotransmitters glutamate and GABA and neuronal glucose metabolism (Sibson et al. 1998, Rothman et al. 2022). This relationship is mechanistically grounded in the pseudo malate-aspartate shuttle model (PMAS) (Rothman et al. 2024). According to this model, glutamate synthesis from glutamine in neurons is directly coupled to glucose oxidation via the malate-aspartate shuttle.

Building upon the PMAS, we developed a computational model that simulates how perturbations in metabolism impact the dynamics of neurotransmitter cycling in the brain.

The dynamics of neurotransmitter cycling were simulated using differential equations representing reactions within a connected system of excitatory neurons, inhibitory neurons, and astrocytes. Key reaction pathways involved in neurotransmitter cycling were identified via mass balance analysis (Rothman et al. 2024) and the principle of metabolic control (Fell 1992), while reactions exerting minimal control over system dynamics were modeled as simple flow-throughs. Reaction equations were parameterized from literature and enzyme database entries.

See the corresponding publication for more details and the underlying equations here: Link to be added.

The model code and relevant tutorials are available here: GitHub

References

● Rothman, Douglas L., et al. "In vivo 13C and 1H‐[13C] MRS studies of neuroenergetics and neurotransmitter cycling, applications to neurological and psychiatric disease and brain cancer." NMR in Biomedicine 32.10 (2019): e4172.
● Sibson, Nicola R., et al. "Stoichiometric coupling of brain glucose metabolism and glutamatergic neuronal activity." Proceedings of the National Academy of Sciences 95.1 (1998): 316-321.
● Rothman, Douglas L., Kevin L. Behar, and Gerald A. Dienel. "Mechanistic stoichiometric relationship between the rates of neurotransmission and neuronal glucose oxidation: Reevaluation of and alternatives to the pseudo‐malate‐aspartate shuttle model." Journal of Neurochemistry 168.5 (2024): 555-591.
● Fell, David A. "Metabolic control analysis: a survey of its theoretical and experimental development." Biochemical Journal 286.Pt 2 (1992): 313.

How to Use This Tool

  • ● The Model tab displays the reactions and their reactants, with the equations for the reaction rates shown below.
  • ● Adjust reaction parameters to test your hypotheses by selecting parameters from the dropdown menu in the Parameters tab and entering their values. You can simultaneously modify as many parameters as you wish.
  • ● You can simulate two conditions (Condition 1 and Condition 2) simultaneously to facilitate easy comparison between a test and a reference condition. You can modify the parameters of either condition by selecting it using the toggle switch.
  • ● Under the Initial Conditions tab, you can modify the starting concentrations of your simulations.
  • ● The model will automatically simulate using the updated values.
  • ● To restore default parameters, click the Reset Settings button.
  • ● To display all adjustable parameters, click the Full Model button.
  • ● Define your own simulation length. Use this option to ensure the simulation runs long enough to reach a new steady state.
  • ● There are two options for displaying the results. Dynamics shows the time series for the full simulation, while End-points displays only the final concentrations as bar plots.
  • ● Select the variables you want to plot, and the graphs will update accordingly.
  • ● Enable Percentage Change to visualize relative changes compared to initial values instead of absolute concentrations.
  • ● To download a plot, hover over it with your cursor to access the Download plot as a PNG option.
  • ● To download the simulation results as an Excel file, click the Download Results button within the Dynamics tab.

Abbreviations & Legend

Metabolites

GLC: glucose

KET: ketone (beta-hydroxybutyrate)

GLN: glutamine

GLU: glutamate

GABA: gamma-aminobutyric acid

ATP: adenosine triphosphate

Kinetic Parameters

Vmax: maximum reaction rate

Tmax: maximum transport rate

Km: Michaelis-Menten constant

KI: Michaelis-Menten constant for inhibition

KT: Michaelis-Menten constant for transport

CMR: cerebral metabolic rate

Enzymes & Processes

PMAS: pseudo malate aspartate shuttle

PAG: phosphate-activated glutaminase

GS: glutamine synthetase

GDH: glutamate dehydrogenase

GT: GABA transaminase

GAD: glutamate decarboxylase

anapl: anaplerosis

Sub- and Superscript Notation

_e: excitatory neuronal

_i: inhibitory neuronal

_a: astrocytic

_v: vesicular

_c: cytosolic

_b: brain

_p: plasma

_syn: synaptic

_trans: transport

_out: efflux