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Aberrant adenosine signaling in patients with focal cortical dysplasia

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Abstract

Focal cortical dysplasia (FCD), a common malformation of cortical development, is frequently associated with pharmacoresistant epilepsy in both children and adults. Adenosine is an inhibitory modulator of brain activity and a prospective anti-seizure agent with potential for clinical translation. Our previous results demonstrated that the major adenosine-metabolizing enzyme adenosine kinase (ADK) was upregulated in balloon cells (BCs) within FCD type IIB lesions, suggesting that dysfunction of the adenosine system is implicated in the pathophysiology of FCD. In our current study, we therefore performed a comprehensive analysis of adenosine signaling in surgically resected cortical specimens from patients with FCD type I and type II via immunohistochemistry and immunoblot analysis. Adenosine enzyme signaling was assessed by quantifying the levels of the key enzymes of adenosine metabolism, i.e., ADK, adenosine deaminase (ADA), and ecto-5'-nucleotidase (CD73). Adenosine receptor signaling was assessed by quantifying the levels of adenosine A2A receptor (A2AR) and putative downstream mediators of adenosine, namely, glutamate transporter-1 (GLT-1) and mammalian target of rapamycin (mTOR). Within lesions in FCD specimens, we found that the adenosine-metabolizing enzymes ADK and ADA, as well as the adenosine-producing enzyme CD73, were upregulated. We also observed an increase in A2AR density, as well as a decrease in GLT-1 levels and an increase in mTOR levels, in FCD specimens compared with control tissue. These results suggest that dysregulation of the adenosine system is a common pathologic feature of both FCD type I and type II. The adenosine system might therefore be a therapeutic target for the treatment of epilepsy associated with FCD.

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Data Availability

The datasets generated in the current research are available from the corresponding authors on reasonable request.

References

  1. Crino PB (2015) Focal Cortical Dysplasia. Seminars Neurol 35(3):201–8. https://doi.org/10.1055/s-0035-1552617

    Article  Google Scholar 

  2. Blümcke I, Thom M, Aronica E et al (2011) The clinicopathologic spectrum of focal cortical dysplasias: a consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission. Epilepsia. 52(1):158–74. https://doi.org/10.1111/j.1528-1167.2010.02777.x

    Article  PubMed  Google Scholar 

  3. Tassi L, Garbelli R, Colombo N et al (2010) Type I focal cortical dysplasia: surgical outcome is related to histopathology. Epileptic Dis : Int Epilepsy J Videotape. 12(3):181–91. https://doi.org/10.1684/epd.2010.0327

    Article  Google Scholar 

  4. Guerrini R, Duchowny M, Jayakar P et al (2015) Diagnostic methods and treatment options for focal cortical dysplasia. Epilepsia. 56(11):1669–86. https://doi.org/10.1111/epi.13200

    Article  CAS  PubMed  Google Scholar 

  5. Tassi L, Colombo N, Garbelli R et al (2002) Focal cortical dysplasia: neuropathological subtypes, EEG, neuroimaging and surgical outcome. Brain : J Neurol 125(Pt 8):1719–32. https://doi.org/10.1093/brain/awf175

    Article  CAS  Google Scholar 

  6. Lim JS, Kim WI, Kang HC et al (2015) Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy. Nat Med 21(4):395–400. https://doi.org/10.1038/nm.3824

    Article  CAS  PubMed  Google Scholar 

  7. Nakashima M, Saitsu H, Takei N et al (2015) Somatic Mutations in the MTOR gene cause focal cortical dysplasia type IIb. Ann Neurol 78(3):375–86. https://doi.org/10.1002/ana.24444

    Article  CAS  PubMed  Google Scholar 

  8. Weichhart T, Säemann MD (2009) The multiple facets of mTOR in immunity. Trends Immunol 30(5):218–26. https://doi.org/10.1016/j.it.2009.02.002

    Article  CAS  PubMed  Google Scholar 

  9. Maldonado M, Baybis M, Newman D et al (2003) Expression of ICAM-1, TNF-alpha, NF kappa B, and MAP kinase in tubers of the tuberous sclerosis complex. Neurobiol Dis 14(2):279–90. https://doi.org/10.1016/s0969-9961(03)00127-x

    Article  CAS  PubMed  Google Scholar 

  10. Boer K, Spliet WG, van Rijen PC, Redeker S, Troost D, Aronica E (2006) Evidence of activated microglia in focal cortical dysplasia. J Neuroimmunol 173(1–2):188–95. https://doi.org/10.1016/j.jneuroim.2006.01.002

    Article  CAS  PubMed  Google Scholar 

  11. Cepeda C, André VM, Levine MS et al (2006) Epileptogenesis in pediatric cortical dysplasia: the dysmature cerebral developmental hypothesis. Epilepsy Behavior : E&B. 9(2):219–35. https://doi.org/10.1016/j.yebeh.2006.05.012

    Article  Google Scholar 

  12. Hammers A, Koepp MJ, Richardson MP et al (2001) Central benzodiazepine receptors in malformations of cortical development: A quantitative study. Brain : J Neurol 124(Pt 8):1555–65. https://doi.org/10.1093/brain/124.8.1555

    Article  CAS  Google Scholar 

  13. Luan G, Gao Q, Zhai F et al (2015) Adenosine kinase expression in cortical dysplasia with balloon cells: analysis of developmental lineage of cell types. J Neuropathol Exp Neurol 74(2):132–47. https://doi.org/10.1097/nen.0000000000000156

    Article  CAS  PubMed  Google Scholar 

  14. Li T, Ren G, Lusardi T et al (2008) Adenosine kinase is a target for the prediction and prevention of epileptogenesis in mice. J Clin Investig 118(2):571–82. https://doi.org/10.1172/jci33737

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Masino SA, Li T, Theofilas P et al (2011) A ketogenic diet suppresses seizures in mice through adenosine A1 receptors. J Clin Investig 121(7):2679–83. https://doi.org/10.1172/jci57813

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Li T, Quan Lan J, Fredholm BB, Simon RP, Boison D (2007) Adenosine dysfunction in astrogliosis: cause for seizure generation? Neuron glia Biol 3(4):353–66. https://doi.org/10.1017/s1740925x0800015x

    Article  PubMed  PubMed Central  Google Scholar 

  17. Moschovos C, Kostopoulos G, Papatheodoropoulos C (2012) Endogenous adenosine induces NMDA receptor-independent persistent epileptiform discharges in dorsal and ventral hippocampus via activation of A2 receptors. Epilepsy Res 100(1–2):157–67. https://doi.org/10.1016/j.eplepsyres.2012.02.012

    Article  CAS  PubMed  Google Scholar 

  18. Boison D (2016) Adenosinergic signaling in epilepsy. Neuropharmacology. 104:131–9. https://doi.org/10.1016/j.neuropharm.2015.08.046

    Article  CAS  PubMed  Google Scholar 

  19. Guo M, Li T (2022) Adenosine Dysfunction in Epilepsy and Associated Comorbidities. Curr Drug Targets 23(4):344–357. https://doi.org/10.2174/1389450122666210928145258

    Article  CAS  PubMed  Google Scholar 

  20. Guo M, Xie P, Liu S, Luan G, Li T (2022) Epilepsy and Autism Spectrum Disorder (ASD): The underlying Mechanisms and Therapy Targets related with Adenosine. Curr Neuropharmacol. https://doi.org/10.2174/1570159x20666220706100136

    Article  Google Scholar 

  21. Lopes LV, Cunha RA, Kull B, Fredholm BB, Ribeiro JA (2002) Adenosine A(2A) receptor facilitation of hippocampal synaptic transmission is dependent on tonic A(1) receptor inhibition. Neuroscience. 112(2):319–29. https://doi.org/10.1016/s0306-4522(02)00080-5

    Article  CAS  PubMed  Google Scholar 

  22. Matos M, Augusto E, Agostinho P, Cunha RA, Chen JF (2013) Antagonistic interaction between adenosine A2A receptors and Na+/K+-ATPase-α2 controlling glutamate uptake in astrocytes. J Neurosci : Off J Soc Neurosci 33(47):18492–502. https://doi.org/10.1523/jneurosci.1828-13.2013

    Article  CAS  Google Scholar 

  23. Gonçalves FQ, Lopes JP, Silva HB et al (2019) Synaptic and memory dysfunction in a β-amyloid model of early Alzheimer’s disease depends on increased formation of ATP-derived extracellular adenosine. Neurobiol Dis 132:104570. https://doi.org/10.1016/j.nbd.2019.104570

    Article  CAS  PubMed  Google Scholar 

  24. Stockwell J, Jakova E, Cayabyab FS (2017) Adenosine A1 and A2A Receptors in the Brain: Current Research and Their Role in Neurodegeneration. Molecules (Basel, Switzerland). 22(4)https://doi.org/10.3390/molecules22040676

  25. Matos M, Augusto E, Santos-Rodrigues AD et al (2012) Adenosine A2A receptors modulate glutamate uptake in cultured astrocytes and gliosomes. Glia. 60(5):702–16. https://doi.org/10.1002/glia.22290

    Article  PubMed  Google Scholar 

  26. Matos M, Shen HY, Augusto E et al (2015) Deletion of adenosine A2A receptors from astrocytes disrupts glutamate homeostasis leading to psychomotor and cognitive impairment: relevance to schizophrenia. Biol Psych 78(11):763–74. https://doi.org/10.1016/j.biopsych.2015.02.026

    Article  CAS  Google Scholar 

  27. He X, Chen F, Zhang Y et al (2020) Upregulation of adenosine A2A receptor and downregulation of GLT1 is associated with neuronal cell death in Rasmussen’s encephalitis. Brain Pathol (Zurich, Switzerland). 30(2):246–260. https://doi.org/10.1111/bpa.12770

    Article  CAS  Google Scholar 

  28. Boison D (2008) The adenosine kinase hypothesis of epileptogenesis. Progress Neurobiol 84(3):249–62. https://doi.org/10.1016/j.pneurobio.2007.12.002

    Article  CAS  Google Scholar 

  29. Boison D (2012) Adenosine dysfunction in epilepsy. Glia. 60(8):1234–1243

    Article  PubMed  Google Scholar 

  30. Li T, Lytle N, Lan JQ, Sandau US, Boison D (2012) Local disruption of glial adenosine homeostasis in mice associates with focal electrographic seizures: a first step in epileptogenesis? Glia. 60(1):83–95. https://doi.org/10.1002/glia.21250

    Article  PubMed  Google Scholar 

  31. de Groot M, Iyer A, Zurolo E et al (2012) Overexpression of ADK in human astrocytic tumors and peritumoral tissue is related to tumor-associated epilepsy. Epilepsia. 53(1):58–66. https://doi.org/10.1111/j.1528-1167.2011.03306.x

    Article  CAS  PubMed  Google Scholar 

  32. Zhang Y, Wang X, Tang C et al (2022) Genetic variations of adenosine kinase as predictable biomarkers of efficacy of vagus nerve stimulation in patients with pharmacoresistant epilepsy. J Neurosurg. 136(3):726–735. https://doi.org/10.3171/2021.3.JNS21141

    Article  CAS  PubMed  Google Scholar 

  33. Luan G, Gao Q, Guan Y et al (2013) Upregulation of adenosine kinase in Rasmussen encephalitis. J Neuropathol Exp Neurol 72(11):1000–8. https://doi.org/10.1097/01.jnen.0000435369.39388.5c

    Article  CAS  PubMed  Google Scholar 

  34. Luan G, Wang X, Gao Q et al (2017) Upregulation of Neuronal Adenosine A1 Receptor in Human Rasmussen Encephalitis. J Neuropathol Exp Neurol 76(8):720–731. https://doi.org/10.1093/jnen/nlx053

    Article  CAS  PubMed  Google Scholar 

  35. Glass M, Faull RL, Bullock JY et al (1996) Loss of A1 adenosine receptors in human temporal lobe epilepsy. Brain Res. 710(1–2):56–68

    Article  CAS  PubMed  Google Scholar 

  36. Boison D (2013) Adenosine kinase: exploitation for therapeutic gain. Pharmacol Rev 65(3):906–43. https://doi.org/10.1124/pr.112.006361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Shi L, Wu Z, Miao J et al (2019) Adenosine interaction with adenosine receptor A2a promotes gastric cancer metastasis by enhancing PI3K-AKT-mTOR signaling. Mole Biol Cell 30(19):2527–2534. https://doi.org/10.1091/mbc.E19-03-0136

    Article  CAS  Google Scholar 

  38. Liu G, Yang S, Liu Y et al (2022) The adenosine-A2a receptor regulates the radioresistance of gastric cancer via PI3K-AKT-mTOR pathway. Int J Clin Oncol 27(5):911–920. https://doi.org/10.1007/s10147-022-02123-x

    Article  CAS  PubMed  Google Scholar 

  39. Palmini A, Najm I, Avanzini G et al (2004) Terminology and classification of the cortical dysplasias. Neurology. 62(6 Suppl 3):S2-8. https://doi.org/10.1212/01.wnl.0000114507.30388.7e

    Article  CAS  PubMed  Google Scholar 

  40. Luan G, Gao Q, Zhai F, Chen Y, Li T (2016) Upregulation of HMGB1, toll-like receptor and RAGE in human Rasmussen’s encephalitis. Epilepsy Res 123:36–49. https://doi.org/10.1016/j.eplepsyres.2016.03.005

    Article  CAS  PubMed  Google Scholar 

  41. Bautista JF, Lüders HO (2000) Semiological seizure classification: relevance to pediatric epilepsy. Epileptic Disord : Int epilepsy J Videotape. 2(1):65-72; discussion 73

  42. Lüders H, Acharya J, Baumgartner C et al (1998) Semiological seizure classification. Epilepsia. 39(9):1006–13. https://doi.org/10.1111/j.1528-1157.1998.tb01452.x

    Article  PubMed  Google Scholar 

  43. Li T, Steinbeck JA, Lusardi T et al (2007) Suppression of kindling epileptogenesis by adenosine releasing stem cell-derived brain implants. Brain : J Neurol 130(Pt 5):1276–88. https://doi.org/10.1093/brain/awm057

    Article  Google Scholar 

  44. Yegutkin GG, Boison D (2022) ATP and Adenosine Metabolism in Cancer: Exploitation for Therapeutic Gain. Pharmacol Rev 74(3):797–822. https://doi.org/10.1124/pharmrev.121.000528

    Article  CAS  PubMed  Google Scholar 

  45. Boison D, Yegutkin GG (2019) Adenosine metabolism: emerging concepts for cancer therapy. Cancer Cell 36:582–596

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. During MJ, Spencer DD (1992) Adenosine: a potential mediator of seizure arrest and postictal refractoriness. Ann Neurol 32(5):618–24

    Article  CAS  PubMed  Google Scholar 

  47. Boison D, Chen JF, Fredholm BB (2010) Adenosine signaling and function in glial cells. Cell Death Differ. 17(7):1071–82. https://doi.org/10.1038/cdd.2009.131

    Article  CAS  PubMed  Google Scholar 

  48. Fedele DE, Koch P, Brüstle O et al (2004) Engineering embryonic stem cell derived glia for adenosine delivery. Neurosci Lett. 370(2–3):160–165

    Article  CAS  PubMed  Google Scholar 

  49. Patodia S, Paradiso B, Garcia M et al (2020) Adenosine kinase and adenosine receptors A(1) R and A(2A) R in temporal lobe epilepsy and hippocampal sclerosis and association with risk factors for SUDEP. Epilepsia. 61(4):787–797. https://doi.org/10.1111/epi.16487

    Article  CAS  PubMed  Google Scholar 

  50. Aronica E, Zurolo E, Iyer A et al (2011) Upregulation of adenosine kinase in astrocytes in experimental and human temporal lobe epilepsy. Epilepsia. 52(9):1645–55. https://doi.org/10.1111/j.1528-1167.2011.03115.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Cui XA, Singh B, Park J, Gupta RS (2009) Subcellular localization of adenosine kinase in mammalian cells: The long isoform of AdK is localized in the nucleus. Biochem Biophys Res Commun 388(1):46–50. https://doi.org/10.1016/j.bbrc.2009.07.106

    Article  CAS  PubMed  Google Scholar 

  52. Aronica E, Sandau US, Iyer A, Boison D (2013) Glial adenosine kinase–a neuropathological marker of the epileptic brain. Neurochem Int 63(7):688–95. https://doi.org/10.1016/j.neuint.2013.01.028

    Article  CAS  PubMed  Google Scholar 

  53. Studer FE, Fedele DE, Marowsky A, et al (2006) Shift of adenosine kinase expression from neurons to astrocytes during postnatal development suggests dual functionality of the enzyme. Neuroscience. 142(1):125-37. S0306-4522(06)00812-8 [pii] https://doi.org/10.1016/j.neuroscience.2006.06.016

  54. Gomez-Castro F, Zappettini S, Pressey JC et al (2021) Convergence of adenosine and GABA signaling for synapse stabilization during development. Science (New York, NY) 374(6568):eabk2055. https://doi.org/10.1126/science.abk2055

    Article  CAS  Google Scholar 

  55. Silva CG, Métin C, Fazeli W et al (2013) Adenosine receptor antagonists including caffeine alter fetal brain development in mice. Sci Transl Med 5(197):197ra104. https://doi.org/10.1126/scitranslmed.3006258

    Article  CAS  PubMed  Google Scholar 

  56. Alçada-Morais S, Gonçalves N, Moreno-Juan V et al (1991) 2021 Adenosine A2A Receptors Contribute to the Radial Migration of Cortical Projection Neurons through the Regulation of Neuronal Polarization and Axon Formation. Cerebral Cortex (New York, NY 1991) 31(12):5652–5663. https://doi.org/10.1093/cercor/bhab188

    Article  Google Scholar 

  57. Barros-Barbosa AR, Ferreirinha F, Oliveira  et al (2016) Adenosine A(2A) receptor and ecto-5’-nucleotidase/CD73 are upregulated in hippocampal astrocytes of human patients with mesial temporal lobe epilepsy (MTLE). Purinergic Signal 12(4):719–734. https://doi.org/10.1007/s11302-016-9535-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Silva CG, Porciúncula LO, Canas PM, Oliveira CR, Cunha RA (2007) Blockade of adenosine A(2A) receptors prevents staurosporine-induced apoptosis of rat hippocampal neurons. Neurobiol Dis 27(2):182–9. https://doi.org/10.1016/j.nbd.2007.04.018

    Article  CAS  PubMed  Google Scholar 

  59. Popoli P, Frank C, Tebano MT et al (2003) Modulation of glutamate release and excitotoxicity by adenosine A2A receptors. Neurology. 61(11 Suppl 6):S69-71. https://doi.org/10.1212/01.wnl.0000095216.89483.a2

    Article  CAS  PubMed  Google Scholar 

  60. D’Alimonte I, D’Auro M, Citraro R et al (2009) Altered distribution and function of A2A adenosine receptors in the brain of WAG/Rij rats with genetic absence epilepsy, before and after appearance of the disease. Eur J Neurosci 30(6):1023–35. https://doi.org/10.1111/j.1460-9568.2009.06897.x

    Article  PubMed  Google Scholar 

  61. Li X, Kang H, Liu X, et al 2012 Effect of adenosine A2A receptor antagonist ZM241385 on amygdala-kindled seizures and progression of amygdala kindling. Journal of Huazhong University of Science and Technology Medical sciences = Hua zhong ke ji da xue xue bao Yi xue Ying De wen ban = Huazhong keji daxue xuebao Yixue Yingdewen ban. 32(2):257-264. https://doi.org/10.1007/s11596-012-0046-2

  62. Tescarollo FC, Rombo DM, DeLiberto LK et al (2020) Role of Adenosine in Epilepsy and Seizures. J Caffeine Adenosine Res 10(2):45–60. https://doi.org/10.1089/caff.2019.0022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Xu X, Beleza RO, Gonçalves FQ et al (2022) Adenosine A(2A) receptors control synaptic remodeling in the adult brain. Sci Rep 12(1):14690. https://doi.org/10.1038/s41598-022-18884-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. El Yacoubi M, Ledent C, Parmentier M, Daoust M, Costentin J, Vaugeois J (2001) Absence of the adenosine A(2A) receptor or its chronic blockade decrease ethanol withdrawal-induced seizures in mice. Neuropharmacology. 40(3):424–32. https://doi.org/10.1016/s0028-3908(00)00173-8

    Article  PubMed  Google Scholar 

  65. El Yacoubi M, Ledent C, Parmentier M, Costentin J, Vaugeois JM (2008) Evidence for the involvement of the adenosine A(2A) receptor in the lowered susceptibility to pentylenetetrazol-induced seizures produced in mice by long-term treatment with caffeine. Neuropharmacology. 55(1):35–40. https://doi.org/10.1016/j.neuropharm.2008.04.007

    Article  CAS  PubMed  Google Scholar 

  66. Hosseinmardi N, Mirnajafi-Zadeh J, Fathollahi Y, Shahabi P (2007) The role of adenosine A1 and A2A receptors of entorhinal cortex on piriform cortex kindled seizures in rats. Pharmacol Res 56(2):110–7. https://doi.org/10.1016/j.phrs.2007.04.011

    Article  CAS  PubMed  Google Scholar 

  67. Zeraati M, Mirnajafi-Zadeh J, Fathollahi Y, Namvar S, Rezvani ME (2006) Adenosine A1 and A2A receptors of hippocampal CA1 region have opposite effects on piriform cortex kindled seizures in rats. Seizure. 15(1):41–8. https://doi.org/10.1016/j.seizure.2005.10.006

    Article  PubMed  Google Scholar 

  68. Etherington LA, Frenguelli BG (2004) Endogenous adenosine modulates epileptiform activity in rat hippocampus in a receptor subtype-dependent manner. Eur J Neurosci 19(9):2539–50. https://doi.org/10.1111/j.0953-816X.2004.03355.x

    Article  PubMed  Google Scholar 

  69. El Yacoubi M, Ledent C, Parmentier M, Costentin J, Vaugeois JM (2009) Adenosine A2A receptor deficient mice are partially resistant to limbic seizures. Naunyn-Schmiedeberg’s arch Pharmacol 380(3):223–32. https://doi.org/10.1007/s00210-009-0426-8

    Article  CAS  Google Scholar 

  70. Lopes LV, Cunha RA, Ribeiro JA (1999) Cross talk between A(1) and A(2A) adenosine receptors in the hippocampus and cortex of young adult and old rats. J Neurophysiol 82(6):3196–203. https://doi.org/10.1152/jn.1999.82.6.3196

    Article  CAS  PubMed  Google Scholar 

  71. Canas PM, Porciúncula LO, Simões AP, et al (2018) Neuronal Adenosine A2A Receptors Are Critical Mediators of Neurodegeneration Triggered by Convulsions. eNeuro. 5(6) https://doi.org/10.1523/eneuro.0385-18.2018

  72. Cunha RA (2016) How does adenosine control neuronal dysfunction and neurodegeneration? J Neurochem 139(6):1019–1055. https://doi.org/10.1111/jnc.13724

    Article  CAS  PubMed  Google Scholar 

  73. Gomes CV, Kaster MP, Tome AR, Agostinho PM, Cunha RA (2011) Adenosine receptors and brain diseases: neuroprotection and neurodegeneration. Biochim Biophys Acta. May 1808(5):1380-99. S0005-2736(10)00423-2 [pii] https://doi.org/10.1016/j.bbamem.2010.12.001

  74. Benarroch EE (2010) Glutamate transporters: diversity, function, and involvement in neurologic disease. Neurology. 74(3):259–64. https://doi.org/10.1212/WNL.0b013e3181cc89e3

    Article  PubMed  Google Scholar 

  75. Aronica E, van Vliet EA, Hendriksen E, Troost D, Lopes da Silva FH, Gorter JA (2001) Cystatin C, a cysteine protease inhibitor, is persistently up-regulated in neurons and glia in a rat model for mesial temporal lobe epilepsy. The European journal of neuroscience 14(9):1485–91. https://doi.org/10.1046/j.0953-816x.2001.01779.x

    Article  CAS  PubMed  Google Scholar 

  76. Beach TG, Woodhurst WB, MacDonald DB, Jones MW (1995) Reactive microglia in hippocampal sclerosis associated with human temporal lobe epilepsy. Neurosci Lett 191(1–2):27–30. https://doi.org/10.1016/0304-3940(94)11548-1

    Article  CAS  PubMed  Google Scholar 

  77. Niquet J, Ben-Ari Y, Represa A (1994) Glial reaction after seizure induced hippocampal lesion: immunohistochemical characterization of proliferating glial cells. J Neurocytol 23(10):641–56. https://doi.org/10.1007/bf01191558

    Article  CAS  PubMed  Google Scholar 

  78. Taniwaki Y, Kato M, Araki T, Kobayashi T (1996) Microglial activation by epileptic activities through the propagation pathway of kainic acid-induced hippocampal seizures in the rat. Neurosci Lett 217(1):29–32. https://doi.org/10.1016/0304-3940(96)13062-7

    Article  CAS  PubMed  Google Scholar 

  79. Aronica E, Gorter JA, Redeker S et al (2005) Distribution, characterization and clinical significance of microglia in glioneuronal tumours from patients with chronic intractable epilepsy. Neuropathol Appl Neurobiol 31(3):280–91. https://doi.org/10.1111/j.1365-2990.2004.00636.x

    Article  CAS  PubMed  Google Scholar 

  80. Iffland PH 2nd, Crino PB (2017) Focal Cortical Dysplasia: Gene Mutations, Cell Signaling, and Therapeutic Implications. Ann Rev Pathol 12:547–571. https://doi.org/10.1146/annurev-pathol-052016-100138

    Article  CAS  Google Scholar 

  81. Mossmann D, Park S, Hall MN (2018) mTOR signalling and cellular metabolism are mutual determinants in cancer. Nat Rev Cancer. 18(12):744–757. https://doi.org/10.1038/s41568-018-0074-8

    Article  CAS  PubMed  Google Scholar 

  82. Curatolo P, Moavero R, van Scheppingen J, Aronica E (2018) mTOR dysregulation and tuberous sclerosis-related epilepsy. Exp Rev Neurotherapeut 18(3):185–201. https://doi.org/10.1080/14737175.2018.1428562

    Article  CAS  Google Scholar 

  83. Hodges SL, Lugo JN (2020) Therapeutic role of targeting mTOR signaling and neuroinflammation in epilepsy. Epilepsy Res 161:106282. https://doi.org/10.1016/j.eplepsyres.2020.106282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Inoki K, Kim J, Guan KL (2012) AMPK and mTOR in cellular energy homeostasis and drug targets. Ann Rev Pharmacol Toxicol 52:381–400. https://doi.org/10.1146/annurev-pharmtox-010611-134537

    Article  CAS  Google Scholar 

  85. Yan Y, Mukherjee S, Harikumar KG et al (2021) Structure of an AMPK complex in an inactive, ATP-bound state. Science (New York, NY). 373(6553):413–419. https://doi.org/10.1126/science.abe7565

    Article  CAS  Google Scholar 

  86. Marsan E, Baulac S (2018) Review: Mechanistic target of rapamycin (mTOR) pathway, focal cortical dysplasia and epilepsy. Neuropathol Appl Neurobiol 44(1):6–17. https://doi.org/10.1111/nan.12463

    Article  CAS  PubMed  Google Scholar 

  87. Ljungberg MC, Bhattacharjee MB, Lu Y et al (2006) Activation of mammalian target of rapamycin in cytomegalic neurons of human cortical dysplasia. Ann Neurol 60(4):420–9. https://doi.org/10.1002/ana.20949

    Article  CAS  PubMed  Google Scholar 

  88. Liu J, Reeves C, Michalak Z et al (2014) Evidence for mTOR pathway activation in a spectrum of epilepsy-associated pathologies. Acta Neuropathol Commun 2:71. https://doi.org/10.1186/2051-5960-2-71

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Natural Science Foundation of China (grant numbers 81571275 and 11932003) and the National Institutes of Health (grant numbers NS065957, NS103740, and NS127846).

Funding

This work was supported by the National Natural Science Foundation of China (grant numbers 81571275 and 11932003) and the National Institutes of Health (grant numbers NS065957, NS103740, and NS127846).

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  1. Mengyi Guo, Jing Zhang,and Jing Wang co-first authors who contributed equally to this work.

Authors and Affiliations

  1. Department of Brain Institute, Center of Epilepsy, Beijing Institute for Brain Disorders, Beijing Key Laboratory of Epilepsy Research, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China

    Mengyi Guo, Jing Zhang, Xiongfei Wang, Qing Gao, Chongyang Tang, Jiahui Deng, Zhonghua Xiong, Xiangru Kong, Yuguang Guan, Jian Zhou, Guoming Luan & Tianfu Li

  2. Department of Neurology, Center of Epilepsy, Beijing Institute for Brain Disorders, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China

    Mengyi Guo, Jing Zhang, Jing Wang, Zhonghua Xiong & Tianfu Li

  3. Department of Neurosurgery, Center of Epilepsy, Beijing Institute for Brain Disorders, Beijing Key Laboratory of Epilepsy Research, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China

    Xiongfei Wang, Chongyang Tang, Yuguang Guan, Jian Zhou & Guoming Luan

  4. Department of Neurosurgery, Robert Wood Johnson & New Jersey Medical Schools, Rutgers University, Piscataway, NJ, 08854, USA

    Detlev Boison

Authors
  1. Mengyi Guo
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  2. Jing Zhang
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  3. Jing Wang
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  4. Xiongfei Wang
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  5. Qing Gao
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  7. Jiahui Deng
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  10. Yuguang Guan
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  11. Jian Zhou
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  12. Detlev Boison
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  13. Guoming Luan
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  14. Tianfu Li
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Contributions

All authors contributed to the study conception and design. The overall experimental design was conceived and supervised by Tianfu Li and Guoming Luan; Mengyi Guo, Jing Zhang, Jing Wang and Xiongfei Wang helped Tianfu Li and Guoming Luan in drafting and preparing the manuscript for submission; Immunohistochemistry, western blot, as well as the analysis of the data were performed by Mengyi Guo, Jing Zhang, Jing Wang, Chongyang Tang, Jiahui Deng, Zhonghua Xiong and Xiangru Kong; Yuguang Guan and Jian Zhou helped in the selection and collection of brain tissues; Detlev Boison provided advice and co-wrote the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Guoming Luan or Tianfu Li.

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Competing Interests

The authors have no relevant financial or non-financial interests to disclose.

Ethics Approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the local ethics committee (Beijing Sanbo Hospital, Capital Medical University, Beijing, China).

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Not applicable.

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Informed consent was obtained from parents or legal guardians of all participants.

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Cite this article

Guo, M., Zhang, J., Wang, J. et al. Aberrant adenosine signaling in patients with focal cortical dysplasia. Mol Neurobiol 60, 4396–4417 (2023). https://doi.org/10.1007/s12035-023-03351-6

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  • DOI: https://doi.org/10.1007/s12035-023-03351-6

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