What is this model for? The main purpose of this model is to
simulate neurotransmitter levels in the brain, focusing on glutamate and gamma-aminobutyric acid
(GABA). Use this tool to test how different interventions – provided they correspond to one of
the modeled reactions – impact 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 (Rothman et
al. 2019). This relationship is mechanistically grounded in the pseudo malate-aspartate shuttle
model (PMAS) (Sibson et al. 1998, 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 this connection between neurotransmitter cycling
rates and energy substrates, we developed a computational model that simulates 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 in a previous work (Rothman
et al. 2024). Using the principle of metabolic control (Fell 1992), we determined which
reactions required dynamic representations for accurate simulation, while reactions exerting
minimal control over system dynamics were modeled as simple flow-throughs. Reaction equations
were parameterized using 13C MRS measurements and enzyme database entries.
The
corresponding work will be published as a preprint soon!
References: - detailed references coming soon!
● 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."
● Sibson, Nicola R., et al. "Stoichiometric coupling of brain glucose metabolism and
glutamatergic neuronal activity.
● 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."
● Fell, David A. "Metabolic control analysis: a survey of its theoretical and experimental
development."
● 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
Dowload
Results button within the
Dynamics tab.
GLN: glutamine
GLU: glutamate
GABA:
gamma-aminobutyric acid
LAC: lactate
BHB:beta-hydroxybutyrate
Vmax: maximum reaction rate
Km:Michaelis-Menten constant
CMRglc: cerebral metabolic rate of
glucose
MAS: pseudo malate aspartate shuttle
PAG:phosphate-activated glutaminase
GS: glutamine
synthetase
GT: GABA transaminase
GAD65/67: glutamate
decarboxylase 65/67_e: excitatory neuronal
_e: excitatory
neuronal
_i: inhibitory neuronal
_a:astrocytic
_s: vesicula
_cyc: cycling
_e0,
_i0, _a0: baseline level/rate
_pmas: GLU-specific fraction
of MAS
_gtmas: GABA-specific fraction of MAS
Default parameter set represents a healthy young adult's brain.
Default initial conditions correspond to steady-state concentrations given the default parameter set.
Use the toggle below to switch between modifying conditions 1 and 2:
Final Concentrations:
This model is part of Neuroblox. Visit at www.neuroblox.org. Contact: botond.antal(at)stonybrook.edu