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 bodys mass, but consumes almost 20% of the bodys 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 70% and area under curve (AUC) by 10%. 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. Key PointsO_LINeurons consume disproportionate amounts of cellular energy relative to their mass, indicating the importance of energy regulation in information processing in the brain. C_LIO_LIAMP activated protein kinase (AMPK) is thought to be the biochemical link between energy consumption in neuronal information processing and synaptic plasticity. C_LIO_LIComputational model investigating the crosstalk between high-frequency glutamatergic calcium signaling and AMPK activation in neurons predicts multistability in AMPK and mammalian target of rapamycin (mTOR) activation. C_LIO_LIOur models predict a frequency-dependent response in AMPK and mTOR activation that also scales according to insulin signaling and energy consumption. The oscillatory behavior depends on both intracellular and extracellular factors, such as energy consumption and insulin signaling. C_LIO_LIThis work elucidates the role of insulin and insulin resistance in regulating neuronal activity, through computational modeling the metabolic response of energy stress resulting from calcium signaling. C_LI