Neuron–astrocyte metabolic coupling facilitates spinal plasticity and maintenance of inflammatory pain
Nature Metabolism, vol. 6, pp. 494–513
Abstract
Long-lasting pain stimuli can trigger maladaptive changes in the spinal cord, reminiscent of plasticity associated with memory formation. Metabolic coupling between astrocytes and neurons has been implicated in neuronal plasticity and memory formation in the central nervous system, but neither its involvement in pathological pain nor in spinal plasticity has been tested. Here we report a form of neuroglia signalling involving spinal astrocytic glycogen dynamics triggered by persistent noxious stimulation via upregulation of the Protein Targeting to Glycogen (PTG) in spinal astrocytes. PTG drove glycogen build-up in astrocytes, and blunting glycogen accumulation and turnover by Ptg gene deletion reduced pain-related behaviours and promoted faster recovery by shortening pain maintenance in mice. Furthermore, mechanistic analyses revealed that glycogen dynamics is a critically required process for maintenance of pain by facilitating neuronal plasticity in spinal lamina 1 neurons. In summary, our study describes a previously unappreciated mechanism of astrocyte-neuron metabolic communication through glycogen breakdown in the spinal cord that fuels spinal neuron hyperexcitability.
Authors 15
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Affiliation as printed
Institute of Pharmacology, Heidelberg University, Heidelberg, Germany
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Affiliation as printed
Institute of Pharmacology, Heidelberg University, Heidelberg, Germany
Oliver Wyman GmbH, Munich, Germany
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Heidelberg University · Grünenthal Group (Germany)
Affiliation as printed
Department of Translational Disease Understanding, Grünenthal GmbH, Aachen, Germany
Institute of Pharmacology, Heidelberg University, Heidelberg, Germany
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Affiliation as printed
Institute of Pharmacology, Heidelberg University, Heidelberg, Germany
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Affiliation as printed
Institute of Pharmacology, Heidelberg University, Heidelberg, Germany
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Indiana University School of Medicine
Affiliation as printed
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA
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Affiliation as printed
Department of Neurobiology, Interdisciplinary Center for Neurosciences (IZN), Heidelberg University, Heidelberg, Germany
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Affiliation as printed
Institute of Pharmacology, Heidelberg University, Heidelberg, Germany
Taconic Biosciences, Leverkusen, Germany
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Affiliation as printed
Institute of Pharmacology, Heidelberg University, Heidelberg, Germany
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Affiliation as printed
Institute of Pharmacology, Heidelberg University, Heidelberg, Germany
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Affiliation as printed
Department of Neurobiology, Interdisciplinary Center for Neurosciences (IZN), Heidelberg University, Heidelberg, Germany
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Affiliation as printed
Dietmar-Hopp-Metabolic Center, Division of Neuropaediatrics and Metabolic Medicine, Heidelberg University, Heidelberg, Germany
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Heidelberg University · European Molecular Biology Laboratory
Affiliation as printed
Institute of Pharmacology, Heidelberg University, Heidelberg, Germany
Molecular Medicine Partnership Unit (MMPU), European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
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Heidelberg University · University Hospital Heidelberg · German Center for Diabetes Research
Affiliation as printed
Department of Endocrinology, Diabetology, Metabolism and Clinical Chemistry (Internal Medicine 1), Heidelberg University Hospital, Heidelberg, Germany
German Center of Diabetes Research (DZD), Neuherberg, Germany
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Jan Siemens corresponding
Heidelberg University · European Molecular Biology Laboratory · European Molecular Biology Laboratory
Affiliation as printed
Institute of Pharmacology, Heidelberg University, Heidelberg, Germany. jan.siemens@pharma.uni-heidelberg.de
Molecular Medicine Partnership Unit (MMPU), European Molecular Biology Laboratory (EMBL), Heidelberg, Germany. jan.siemens@pharma.uni-heidelberg.de
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