Author:

Keywords:

Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, ACTIVATED PROTEIN-KINASE, ENERGY-METABOLISM, NEURONAL SURVIVAL, MITOCHONDRIAL BIOENERGETICS, GLUTAMATE EXCITOTOXICITY, CALCIUM-CONCENTRATION, ATP CONCENTRATION, INDUCED APOPTOSIS, CULTURED NEURONS, MEMBRANE, AMP-Activated Protein Kinases, Adenosine Triphosphate, Animals, Cell Membrane, Cerebellum, Computer Simulation, Energy Metabolism, Glucose, Glucose Transport Proteins, Facilitative, Humans, Models, Neurological, Neurons, Rats, General Science & Technology

Abstract:

Loss of ionic homeostasis during excitotoxic stress depletes ATP levels and activates the AMP-activated protein kinase (AMPK), re-establishing energy production by increased expression of glucose transporters on the plasma membrane. Here, we develop a computational model to test whether this AMPK-mediated glucose import can rapidly restore ATP levels following a transient excitotoxic insult. We demonstrate that a highly compact model, comprising a minimal set of critical reactions, can closely resemble the rapid dynamics and cell-to-cell heterogeneity of ATP levels and AMPK activity, as confirmed by single-cell fluorescence microscopy in rat primary cerebellar neurons exposed to glutamate excitotoxicity. The model further correctly predicted an excitotoxicity-induced elevation of intracellular glucose, and well resembled the delayed recovery and cell-to-cell heterogeneity of experimentally measured glucose dynamics. The model also predicted necrotic bioenergetic collapse and altered calcium dynamics following more severe excitotoxic insults. In conclusion, our data suggest that a minimal set of critical reactions may determine the acute bioenergetic response to transient excitotoxicity and that an AMPK-mediated increase in intracellular glucose may be sufficient to rapidly recover ATP levels following an excitotoxic insult.