Norepinephrine stimulates glycogenolysis in astrocytes to fuel neurons with lactate

Abstract
The mechanism of rapid energy supply to the brain, especially to accommodate the heightened metabolic activity of excited states, is not well-understood. We explored the role of glycogen as a fuel source for neuromodulation using the noradrenergic stimulation of glia in a computational model of the neural-glial-vasculature ensemble (NGV). The detection of norepinephrine (NE) by the astrocyte and the coupled cAMP signal are rapid and largely insensitive to the distance of the locus coeruleus projection release sites from the glia, implying a diminished impact for volume transmission in high affinity receptor transduction systems. Glucosyl-conjugated units liberated from glial glycogen by NE-elicited cAMP second messenger transduction winds sequentially through the glycolytic cascade, generating robust increases in NADH and ATP before pyruvate is finally transformed into lactate. This astrocytic lactate is rapidly exported by monocarboxylate transporters to the associated neuron, demonstrating that the astrocyte-to-neuron lactate shuttle activated by glycogenolysis is a likely fuel source for neuromodulation and enhanced neural activity. Altogether, the energy supply for both astrocytes and neurons can be supplied rapidly by glycogenolysis upon neuromodulatory stimulus.

Citation
Coggan JS, Keller D, Calì C, Lehväslaiho H, Markram H, et al. (2018) Norepinephrine stimulates glycogenolysis in astrocytes to fuel neurons with lactate. PLOS Computational Biology 14: e1006392. Available: http://dx.doi.org/10.1371/journal.pcbi.1006392.

Acknowledgements
Supported by a CRG grant from King Abdullah University of Science and Technology "KAUST-EPFL Alliance for Neuro-inspired High-Performance Computing", as well as ETH Board funding to the Blue Brain Project. Support by the NCCR Synapsy and the Prefargier Foundation to PJM are also acknowledged. Calculations were performed on the EPFL Blue Brain IV BlueGene/Q hosted at the Swiss National Supercomputing Center (CSCS) in Lugano. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Publisher
Public Library of Science (PLoS)

Journal
PLOS Computational Biology

DOI
10.1371/journal.pcbi.1006392

Additional Links
https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1006392

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