Modeling Neurotransmitter Cycling: Predicting Glu and GABA Dynamics in Response to Ketone Body Administration

Motivation: Therapeutic interventions involving ketone bodies are gaining traction in various clinical and experimental settings. One hypothesized mechanism for their efficacy is modulation of glutamate and GABA, the brain's primary excitatory and inhibitory neurotransmitters. However, how ketones influence these neurotransmitters remains unclear, limiting broader therapeutic application. Goal(s): Here, we aimed to explore the mechanism of ketone modulation on neurotransmitter activity and to predict these effects. Approach: We developed a computational model to simulate the temporal dynamics and steady-state concentrations of glutamate and GABA as a function of ketone metabolism across varying conditions. Results: We validated our model using MRS data from ketone administration experiments. Impact: We present the first computational model linking brain substrates to neurotransmitter cycling, providing clinicians and researchers with a tool to test hypotheses and optimize treatments. The model is available to the community via Neuroblox, a brain function modeling platform.