Computational modeling of AMPK and mTOR crosstalk in glutamatergic synapse calcium signaling

Neuronal energy consumption is vital for information processing and memory formation in synapses. The brain consists of just 2% of the human body's mass, but consumes almost 20% of the body's energy budget. Most of this energy is attributed to active transport in ion signaling, with calcium being the canonical second messenger of synaptic transmission. Here, we develop a computational model of synaptic signaling resulting in the activation of two protein kinases critical in metabolic regulation and cell fate, AMP-Activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) and investigate the effect of glutamate stimulus frequency on their dynamics. Our model predicts that frequencies of glutamate stimulus over 10 Hz perturb AMPK and mTOR oscillations at higher magnitudes by up to 36% and change the area under curve (AUC) by 5%. This dynamic difference in AMPK and mTOR activation trajectories potentially differentiates high frequency stimulus bursts from basal neuronal signaling leading to a downstream change in synaptic plasticity. Further, we also investigate the crosstalk between insulin receptor and calcium signaling on AMPK and mTOR activation and predict that the pathways demonstrate multistability dependent on strength of insulin signaling and metabolic consumption rate. Our predictions have implications for improving our understanding of neuronal metabolism, synaptic pruning, and synaptic plasticity.