Neuron-astrocyte metabolic coupling facilitates spinal plasticity and maintenance of inflammatory pain.
Journal
Nature metabolism
ISSN: 2522-5812
Titre abrégé: Nat Metab
Pays: Germany
ID NLM: 101736592
Informations de publication
Date de publication:
05 Mar 2024
05 Mar 2024
Historique:
received:
06
10
2022
accepted:
31
01
2024
medline:
6
3
2024
pubmed:
6
3
2024
entrez:
5
3
2024
Statut:
aheadofprint
Résumé
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.
Identifiants
pubmed: 38443593
doi: 10.1038/s42255-024-01001-2
pii: 10.1038/s42255-024-01001-2
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : European Commission (EC)
ID : ERC-CoG-772395
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : SFB1158
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : SFB1158
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : SFB1158
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : SFB1158
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : SFB1158
Organisme : Human Frontier Science Program (HFSP)
ID : LT000762/2019-L
Informations de copyright
© 2024. The Author(s).
Références
Beard, E., Lengacher, S., Dias, S., Magistretti, P. J. & Finsterwald, C. Astrocytes as key regulators of brain energy metabolism: new therapeutic perspectives. Front. Physiol. 12, 825816 (2021).
pubmed: 35087428
doi: 10.3389/fphys.2021.825816
Kuner, R. & Kuner, T. Cellular circuits in the brain and their modulation in acute and chronic pain. Physiol. Rev. 101, 213–258 (2021).
pubmed: 32525759
doi: 10.1152/physrev.00040.2019
Peirs, C. & Seal, R. P. Neural circuits for pain: recent advances and current views. Science 354, 578–584 (2016).
pubmed: 27811268
doi: 10.1126/science.aaf8933
Kuner, R. & Flor, H. Structural plasticity and reorganisation in chronic pain. Nat. Rev. Neurosci. 18, 20–30 (2016).
pubmed: 27974843
doi: 10.1038/nrn.2016.162
Ransom, B. R. Neuroglia (Oxford Univ. Press, 2012).
Ji, R. R., Donnelly, C. R. & Nedergaard, M. Astrocytes in chronic pain and itch. Nat. Rev. Neurosci. 20, 667–685 (2019).
pubmed: 31537912
pmcid: 6874831
doi: 10.1038/s41583-019-0218-1
Kim, D. S. et al. Profiling of dynamically changed gene expression in dorsal root ganglia post peripheral nerve injury and a critical role of injury-induced glial fibrillary acidic protein in maintenance of pain behaviors [corrected]. Pain 143, 114–122 (2009).
pubmed: 19307059
pmcid: 2743568
doi: 10.1016/j.pain.2009.02.006
Kohro, Y. et al. Spinal astrocytes in superficial laminae gate brainstem descending control of mechanosensory hypersensitivity. Nat. Neurosci. 23, 1376–1387 (2020).
pubmed: 33020652
doi: 10.1038/s41593-020-00713-4
Tsuda, M. et al. JAK-STAT3 pathway regulates spinal astrocyte proliferation and neuropathic pain maintenance in rats. Brain 134, 1127–1139 (2011).
pubmed: 21371995
pmcid: 4571138
doi: 10.1093/brain/awr025
Miyamoto, K., Ishikura, K. I., Kume, K. & Ohsawa, M. Astrocyte-neuron lactate shuttle sensitizes nociceptive transmission in the spinal cord. Glia 67, 27–36 (2019).
pubmed: 30430652
doi: 10.1002/glia.23474
Knight, Z. A. et al. Molecular profiling of activated neurons by phosphorylated ribosome capture. Cell 151, 1126–1137 (2012).
pubmed: 23178128
doi: 10.1016/j.cell.2012.10.039
Hu, X. S. & Matsunami, H. High-throughput odorant receptor deorphanization via phospho-S6 ribosomal protein immunoprecipitation and mRNA profiling. Methods Mol. Biol. 1820, 95–112 (2018).
pubmed: 29884940
doi: 10.1007/978-1-4939-8609-5_8
Delorme, J. et al. Sleep loss drives acetylcholine- and somatostatin interneuron-mediated gating of hippocampal activity to inhibit memory consolidation. Proc. Natl Acad. Sci. USA 118, 1–10 (2021).
doi: 10.1073/pnas.2019318118
Naranjo, J. R. et al. Co-induction of jun B and c-fos in a subset of neurons in the spinal cord. Oncogene 6, 223–227 (1991).
pubmed: 1900356
Capone, F. & Aloisi, A. M. Refinement of pain evaluation techniques. The formalin test. Ann. Ist. Super. Sanita 40, 223–229 (2004).
pubmed: 15536274
Chen, G., Zhang, Y. Q., Qadri, Y. J., Serhan, C. N. & Ji, R. R. Microglia in pain: detrimental and protective roles in pathogenesis and resolution of pain. Neuron 100, 1292–1311 (2018).
pubmed: 30571942
pmcid: 6312407
doi: 10.1016/j.neuron.2018.11.009
Kohno, K. & Tsuda, M. Role of microglia and P2X4 receptors in chronic pain. Pain Rep. 6, e864 (2021).
pubmed: 33981920
pmcid: 8108579
doi: 10.1097/PR9.0000000000000864
Tam, T. H. & Salter, M. W. Purinergic signalling in spinal pain processing. Purinergic Signal. 17, 49–54 (2021).
pubmed: 33169292
doi: 10.1007/s11302-020-09748-5
Printen, J. A., Brady, M. J. & Saltiel, A. R. PTG, a protein phosphatase 1-binding protein with a role in glycogen metabolism. Science 275, 1475–1478 (1997).
pubmed: 9045612
doi: 10.1126/science.275.5305.1475
Allaman, I. & Magistretti, P. Brain Energy Metabolism 4th edn (Academic, 2013).
Brown, A. M., Baltan Tekkok, S. & Ransom, B. R. Energy transfer from astrocytes to axons: the role of CNS glycogen. Neurochem. Int. 45, 529–536 (2004).
pubmed: 15186919
doi: 10.1016/j.neuint.2003.11.005
Vilchez, D. et al. Mechanism suppressing glycogen synthesis in neurons and its demise in progressive myoclonus epilepsy. Nat. Neurosci. 10, 1407–1413 (2007).
pubmed: 17952067
doi: 10.1038/nn1998
Ruchti, E., Roach, P. J., DePaoli-Roach, A. A., Magistretti, P. J. & Allaman, I. Protein targeting to glycogen is a master regulator of glycogen synthesis in astrocytes. IBRO Rep. 1, 46–53 (2016).
pubmed: 30135927
pmcid: 6084890
doi: 10.1016/j.ibror.2016.10.002
Avrampou, K. et al. RGS4 maintains chronic pain symptoms in rodent models. J. Neurosci. 39, 8291–8304 (2019).
pubmed: 31308097
pmcid: 6794935
doi: 10.1523/JNEUROSCI.3154-18.2019
Wu, Y. et al. Pain aversion and anxiety-like behavior occur at different times during the course of chronic inflammatory pain in rats. J. Pain. Res. 10, 2585–2593 (2017).
pubmed: 29158690
pmcid: 5683785
doi: 10.2147/JPR.S139679
Kumar, A., Kaur, H. & Singh, A. Neuropathic pain models caused by damage to central or peripheral nervous system. Pharm. Rep. 70, 206–216 (2018).
doi: 10.1016/j.pharep.2017.09.009
Hanani, M. & Verkhratsky, A. Satellite glial cells and astrocytes, a comparative review. Neurochem. Res. 46, 2525–2537 (2021).
pubmed: 33523395
doi: 10.1007/s11064-021-03255-8
Takahashi, S. et al. The RGD motif in fibronectin is essential for development but dispensable for fibril assembly. J. Cell Biol. 178, 167–178 (2007).
pubmed: 17591922
pmcid: 2064432
doi: 10.1083/jcb.200703021
Srinivasan, R. et al. New transgenic mouse lines for selectively targeting astrocytes and studying calcium signals in astrocyte processes in situ and in vivo. Neuron 92, 1181–1195 (2016).
pubmed: 27939582
pmcid: 5403514
doi: 10.1016/j.neuron.2016.11.030
Turner, P. V., Pang, D. S. & Lofgren, J. L. A review of pain assessment methods in laboratory rodents. Comp. Med. 69, 451–467 (2019).
pubmed: 31896391
pmcid: 6935698
doi: 10.30802/AALAS-CM-19-000042
Basbaum, A. I., Bautista, D. M., Scherrer, G. & Julius, D. Cellular and molecular mechanisms of pain. Cell 139, 267–284 (2009).
pubmed: 19837031
pmcid: 2852643
doi: 10.1016/j.cell.2009.09.028
Boury-Jamot, B. et al. Disrupting astrocyte-neuron lactate transfer persistently reduces conditioned responses to cocaine. Mol. Psychiatry 21, 1070–1076 (2016).
pubmed: 26503760
doi: 10.1038/mp.2015.157
Dringen, R., Gebhardt, R. & Hamprecht, B. Glycogen in astrocytes: possible function as lactate supply for neighboring cells. Brain Res. 623, 208–214 (1993).
pubmed: 8221102
doi: 10.1016/0006-8993(93)91429-V
Falkowska, A. et al. Energy metabolism of the brain, including the cooperation between astrocytes and neurons, especially in the context of glycogen metabolism. Int. J. Mol. Sci. 16, 25959–25981 (2015).
pubmed: 26528968
pmcid: 4661798
doi: 10.3390/ijms161125939
Gao, V. et al. Astrocytic β2-adrenergic receptors mediate hippocampal long-term memory consolidation. Proc. Natl Acad. Sci. USA 113, 8526–8531 (2016).
pubmed: 27402767
pmcid: 4968707
doi: 10.1073/pnas.1605063113
Gibbs, M. E. Role of glycogenolysis in memory and learning: regulation by noradrenaline, serotonin and ATP. Front. Integr. Neurosci. 9, 70 (2015).
pubmed: 26834586
Magistretti, P. J. & Allaman, I. A cellular perspective on brain energy metabolism and functional imaging. Neuron 86, 883–901 (2015).
pubmed: 25996133
doi: 10.1016/j.neuron.2015.03.035
Steinman, M. Q., Gao, V. & Alberini, C. M. The role of lactate-mediated metabolic coupling between astrocytes and neurons in long-term memory formation. Front. Integr. Neurosci. 10, 10 (2016).
pubmed: 26973477
pmcid: 4776217
doi: 10.3389/fnint.2016.00010
Suzuki, A. et al. Astrocyte-neuron lactate transport is required for long-term memory formation. Cell 144, 810–823 (2011).
pubmed: 21376239
pmcid: 3073831
doi: 10.1016/j.cell.2011.02.018
Pike Winer, L. S. & Wu, M. Rapid analysis of glycolytic and oxidative substrate flux of cancer cells in a microplate. PLoS ONE 9, e109916 (2014).
pubmed: 25360519
pmcid: 4215881
doi: 10.1371/journal.pone.0109916
Underwood, E., Redell, J. B., Zhao, J., Moore, A. N. & Dash, P. K. A method for assessing tissue respiration in anatomically defined brain regions. Sci. Rep. 10, 13179 (2020).
pubmed: 32764697
pmcid: 7413397
doi: 10.1038/s41598-020-69867-2
Ikeda, H., Heinke, B., Ruscheweyh, R. & Sandkuhler, J. Synaptic plasticity in spinal lamina I projection neurons that mediate hyperalgesia. Science 299, 1237–1240 (2003).
pubmed: 12595694
doi: 10.1126/science.1080659
Ikeda, H. et al. Synaptic amplifier of inflammatory pain in the spinal dorsal horn. Science 312, 1659–1662 (2006).
pubmed: 16778058
doi: 10.1126/science.1127233
Kuner, R. Spinal excitatory mechanisms of pathological pain. Pain 156, S11–S17 (2015).
pubmed: 25789427
doi: 10.1097/j.pain.0000000000000118
Li, X. H., Miao, H. H. & Zhuo, M. NMDA receptor dependent long-term potentiation in chronic pain. Neurochem. Res. 44, 531–538 (2019).
pubmed: 30109556
doi: 10.1007/s11064-018-2614-8
Karagiannis, A. et al. Lactate is an energy substrate for rodent cortical neurons and enhances their firing activity. eLife 10, e71424 (2021).
pubmed: 34766906
pmcid: 8651295
doi: 10.7554/eLife.71424
Xiao, M. M. et al. Gastrodin protects against chronic inflammatory pain by inhibiting spinal synaptic potentiation. Sci. Rep. 6, 37251 (2016).
pubmed: 27853254
pmcid: 5112517
doi: 10.1038/srep37251
Erlichman, J. S. et al. Inhibition of monocarboxylate transporter 2 in the retrotrapezoid nucleus in rats: a test of the astrocyte-neuron lactate-shuttle hypothesis. J. Neurosci. 28, 4888–4896 (2008).
pubmed: 18463242
pmcid: 2645067
doi: 10.1523/JNEUROSCI.5430-07.2008
Halestrap, A. P. & Denton, R. M. The specificity and metabolic implications of the inhibition of pyruvate transport in isolated mitochondria and intact tissue preparations by alpha-Cyano-4-hydroxycinnamate and related compounds. Biochem. J. 148, 97–106 (1975).
pubmed: 1171687
pmcid: 1165510
doi: 10.1042/bj1480097
Compan, V. et al. Monitoring mitochondrial pyruvate carrier activity in real time using a BRET-based biosensor: investigation of the Warburg effect. Mol. Cell 59, 491–501 (2015).
pubmed: 26253029
doi: 10.1016/j.molcel.2015.06.035
de Castro Abrantes, H. et al. The lactate receptor HCAR1 modulates neuronal network activity through the activation of G(α) and G(βγ) subunits. J. Neurosci. 39, 4422–4433 (2019).
pubmed: 30926749
pmcid: 6554634
doi: 10.1523/JNEUROSCI.2092-18.2019
Ahmed, K. et al. An autocrine lactate loop mediates insulin-dependent inhibition of lipolysis through GPR81. Cell Metab. 11, 311–319 (2010).
pubmed: 20374963
doi: 10.1016/j.cmet.2010.02.012
Zhuo, M. Ionotropic glutamate receptors contribute to pain transmission and chronic pain. Neuropharmacology 112, 228–234 (2017).
pubmed: 27543416
doi: 10.1016/j.neuropharm.2016.08.014
Mulder, G. B. & Pritchett, K. The Morris water maze. Contemp. Top. Lab. Anim. Sci. 42, 49–50 (2003).
pubmed: 14615963
Dedek, A. & Hildebrand, M. E. Advances and barriers in understanding presynaptic N-methyl-D-aspartate receptors in spinal pain processing. Front. Mol. Neurosci. 15, 864502 (2022).
pubmed: 35431805
pmcid: 9008455
doi: 10.3389/fnmol.2022.864502
Kronschlager, M. T. et al. Gliogenic LTP spreads widely in nociceptive pathways. Science 354, 1144–1148 (2016).
pubmed: 27934764
pmcid: 6145441
doi: 10.1126/science.aah5715
Chiang, C. Y., Sessle, B. J. & Dostrovsky, J. O. Role of astrocytes in pain. Neurochem. Res. 37, 2419–2431 (2012).
pubmed: 22638776
doi: 10.1007/s11064-012-0801-6
Allaman, I., Lengacher, S., Magistretti, P. J. & Pellerin, L. A2B receptor activation promotes glycogen synthesis in astrocytes through modulation of gene expression. Am. J. Physiol. Cell Physiol. 284, C696–C704 (2003).
pubmed: 12421692
doi: 10.1152/ajpcell.00202.2002
Dringen, R. & Hamprecht, B. Glucose, insulin, and insulin-like growth factor I regulate the glycogen content of astroglia-rich primary cultures. J. Neurochem. 58, 511–517 (1992).
pubmed: 1729397
doi: 10.1111/j.1471-4159.1992.tb09750.x
Hamai, M., Minokoshi, Y. & Shimazu, T. L-Glutamate and insulin enhance glycogen synthesis in cultured astrocytes from the rat brain through different intracellular mechanisms. J. Neurochem. 73, 400–407 (1999).
pubmed: 10386993
doi: 10.1046/j.1471-4159.1999.0730400.x
Heni, M. et al. Insulin promotes glycogen storage and cell proliferation in primary human astrocytes. PLoS ONE 6, e21594 (2011).
pubmed: 21738722
pmcid: 3124526
doi: 10.1371/journal.pone.0021594
Kum, W., Zhu, S. Q., Ho, S. K., Young, J. D. & Cockram, C. S. Effect of insulin on glucose and glycogen metabolism and leucine incorporation into protein in cultured mouse astrocytes. Glia 6, 264–268 (1992).
pubmed: 1464458
doi: 10.1002/glia.440060404
Sorg, O. & Magistretti, P. J. Vasoactive intestinal peptide and noradrenaline exert long-term control on glycogen levels in astrocytes: blockade by protein synthesis inhibition. J. Neurosci. 12, 4923–4931 (1992).
pubmed: 1334506
pmcid: 6575784
doi: 10.1523/JNEUROSCI.12-12-04923.1992
Keinan, O. et al. Glycogen metabolism links glucose homeostasis to thermogenesis in adipocytes. Nature 599, 296–301 (2021).
pubmed: 34707293
pmcid: 9186421
doi: 10.1038/s41586-021-04019-8
Carmean, C. M., Bobe, A. M., Yu, J. C., Volden, P. A. & Brady, M. J. Refeeding-induced brown adipose tissue glycogen hyper-accumulation in mice is mediated by insulin and catecholamines. PLoS ONE 8, e67807 (2013).
pubmed: 23861810
pmcid: 3701606
doi: 10.1371/journal.pone.0067807
Tuerkischer, E. & Wertheimer, E. Factors influencing deposition of glycogen in adipose tissue of the rat. J. Physiol. 104, 361–365 (1946).
pubmed: 16991691
pmcid: 1393576
doi: 10.1113/jphysiol.1946.sp004128
Sada, N., Lee, S., Katsu, T., Otsuki, T. & Inoue, T. Epilepsy treatment. Targeting LDH enzymes with a stiripentol analog to treat epilepsy. Science 347, 1362–1367 (2015).
pubmed: 25792327
doi: 10.1126/science.aaa1299
Tang, F. et al. Lactate-mediated glia-neuronal signalling in the mammalian brain. Nat. Commun. 5, 3284 (2014).
pubmed: 24518663
doi: 10.1038/ncomms4284
Dienel, G. A. The metabolic trinity, glucose-glycogen-lactate, links astrocytes and neurons in brain energetics, signaling, memory, and gene expression. Neurosci. Lett. 637, 18–25 (2017).
pubmed: 25725168
doi: 10.1016/j.neulet.2015.02.052
Andersen, J. V. & Schousboe, A. Milestone review: metabolic dynamics of glutamate and GABA mediated neurotransmission – the essential roles of astrocytes. J. Neurochem. 166, 109–137 (2023).
pubmed: 36919769
doi: 10.1111/jnc.15811
Zeilhofer, H. U., Mohler, H. & Di Lio, A. GABAergic analgesia: new insights from mutant mice and subtype-selective agonists. Trends Pharmacol. Sci. 30, 397–402 (2009).
pubmed: 19616317
doi: 10.1016/j.tips.2009.05.007
Foley, K., McKee, C., Nairn, A. C. & Xia, H. Regulation of synaptic transmission and plasticity by protein phosphatase 1. J. Neurosci. 41, 3040–3050 (2021).
pubmed: 33827970
pmcid: 8026358
doi: 10.1523/JNEUROSCI.2026-20.2021
Genoux, D. et al. Protein phosphatase 1 is a molecular constraint on learning and memory. Nature 418, 970–975 (2002).
pubmed: 12198546
doi: 10.1038/nature00928
Noyes, N. C., Phan, A. & Davis, R. L. Memory suppressor genes: modulating acquisition, consolidation, and forgetting. Neuron 109, 3211–3227 (2021).
pubmed: 34450024
pmcid: 8542634
doi: 10.1016/j.neuron.2021.08.001
Yang, H. et al. Protein phosphatase-1 inhibitor-2 is a novel memory suppressor. J. Neurosci. 35, 15082–15087 (2015).
pubmed: 26558779
pmcid: 4642240
doi: 10.1523/JNEUROSCI.1865-15.2015
Irimia, J. M. et al. Impaired glucose tolerance and predisposition to the fasted state in liver glycogen synthase knock-out mice. J. Biol. Chem. 285, 12851–12861 (2010).
pubmed: 20178984
pmcid: 2857087
doi: 10.1074/jbc.M110.106534
Picelli, S. et al. Full-length RNA-seq from single cells using Smart-seq2. Nat. Protoc. 9, 171–181 (2014).
pubmed: 24385147
doi: 10.1038/nprot.2014.006
Watakabe, A. et al. Comparative analysis of layer-specific genes in mammalian neocortex. Cereb. Cortex 17, 1918–1933 (2007).
pubmed: 17065549
doi: 10.1093/cercor/bhl102
Berg, S. et al. ilastik: interactive machine learning for (bio)image analysis. Nat. Methods 16, 1226–1232 (2019).
pubmed: 31570887
doi: 10.1038/s41592-019-0582-9
Stosser, S., Agarwal, N., Tappe-Theodor, A., Yanagisawa, M. & Kuner, R. Dissecting the functional significance of endothelin A receptors in peripheral nociceptors in vivo via conditional gene deletion. Pain 148, 206–214 (2010).
pubmed: 19879049
doi: 10.1016/j.pain.2009.09.024
Dana, H. et al. Sensitive red protein calcium indicators for imaging neural activity. eLife 5, e12727 (2016).
pubmed: 27011354
pmcid: 4846379
doi: 10.7554/eLife.12727
Hjukse, J. B. et al. Increased membrane Ca
pubmed: 37564028
doi: 10.1002/glia.24450
Bengtson, C. P., Freitag, H. E., Weislogel, J. M. & Bading, H. Nuclear calcium sensors reveal that repetition of trains of synaptic stimuli boosts nuclear calcium signaling in CA1 pyramidal neurons. Biophys. J. 99, 4066–4077 (2010).
pubmed: 21156150
pmcid: 3000507
doi: 10.1016/j.bpj.2010.10.044
McClure, C., Cole, K. L., Wulff, P., Klugmann, M. & Murray, A. J. Production and titering of recombinant adeno-associated viral vectors. J. Vis. Exp. 57, e3348 (2011).
Love, M. I., Anders, S., Kim, V. & Huber, W. RNA-seq workflow: gene-level exploratory analysis and differential expression. F1000Res 4, 1070 (2015).
pubmed: 26674615
pmcid: 4670015
doi: 10.12688/f1000research.7035.1