Neuron-astrocyte metabolic coupling facilitates spinal plasticity and maintenance of inflammatory pain.
Sebastián Marty-Lombardi, Shiying Lu, Wojciech Ambroziak, Katrin Schrenk-Siemens, Jialin Wang, Anna A DePaoli-Roach, Anna M Hagenston, Hagen Wende, Anke Tappe-Theodor, Manuela Simonetti, Hilmar Bading, Jürgen G Okun, Rohini Kuner, Thomas Fleming, Jan Siemens
Author Information
Sebastián Marty-Lombardi: Institute of Pharmacology, Heidelberg University, Heidelberg, Germany. ORCID
Shiying Lu: Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.
Wojciech Ambroziak: Institute of Pharmacology, Heidelberg University, Heidelberg, Germany. ORCID
Katrin Schrenk-Siemens: Institute of Pharmacology, Heidelberg University, Heidelberg, Germany. ORCID
Jialin Wang: Institute of Pharmacology, Heidelberg University, Heidelberg, Germany. ORCID
Anna A DePaoli-Roach: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
Anna M Hagenston: Department of Neurobiology, Interdisciplinary Center for Neurosciences (IZN), Heidelberg University, Heidelberg, Germany. ORCID
Hagen Wende: Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.
Anke Tappe-Theodor: Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.
Manuela Simonetti: Institute of Pharmacology, Heidelberg University, Heidelberg, Germany. ORCID
Hilmar Bading: Department of Neurobiology, Interdisciplinary Center for Neurosciences (IZN), Heidelberg University, Heidelberg, Germany. ORCID
Jürgen G Okun: Dietmar-Hopp-Metabolic Center, Division of Neuropaediatrics and Metabolic Medicine, Heidelberg University, Heidelberg, Germany.
Rohini Kuner: Institute of Pharmacology, Heidelberg University, Heidelberg, Germany. ORCID
Thomas Fleming: Department of Endocrinology, Diabetology, Metabolism and Clinical Chemistry (Internal Medicine 1), Heidelberg University Hospital, Heidelberg, Germany. ORCID
Jan Siemens: Institute of Pharmacology, Heidelberg University, Heidelberg, Germany. jan.siemens@pharma.uni-heidelberg.de. ORCID
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.
