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Can gliomas provide insights into promoting synaptogenesis?

Molecular Psychiatry volume 25, pages 1920–1925 (2020)Cite this article

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While many neurological disorders such as autism and Alzheimer’s disease manifest as circuit dysfunctions, gaps in our understanding of how synapses form have challenged regenerative medicine efforts. Recent discoveries that glial tumors form functional synaptic connections with resident neurons provide new avenues to interrogate early mechanisms of synaptogenesis. The further exploration of this aberrant and novel observation could lead to new insights for fundamental neurobiology and aid in designing new treatment strategies for a wide variety of devastating neurodevelopmental and neurodegenerative diseases.

Neuronal communication through synapses is fundamental to neurological health and survival. Most synapses are established prior to birth but continue to be remodeled and formed throughout life during learning and memory. Pathological decrease in synaptic densities is a hallmark of a diverse range of neurodevelopmental, neuropsychiatric, and neurodegenerative conditions including autism, Alzheimer’s Disease (AD) and Parkinson’s Disease (PD) [1,2,3]. While our understanding of molecular machinery found and maintained at established synapses is quite mature (e.g., neurexins, neuroligins), the initiating events coordinating synaptogenesis remain largely unresolved [4]. Elucidating the mechanisms of early synapse formation presents a unique challenge given that vast majority of neural connections are formed during fetal development in utero and are thus inaccessible for longitudinal monitoring [5,6,7]. Deciphering the signals of how neuronal synaptic partners are chosen and the signaling pathways orchestrating the decisions of when and which type of neural connections are established could however profoundly impact our understanding of a wide spectrum of neurological disorders. For the first time, recent studies provide evidence that glioma cells are electrically active and readily form functional synapses with the adult brain that contribute to tumor growth [8, 9]. Consequently, this finding presents an exciting new opportunity to gain insights into long-standing mysteries surrounding synaptogenesis.

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Fig. 1: Parallels between neurodevelopment and glioblastoma biology.
Fig. 2: Deciphering molecular regulators of synapse formation by studying gliomas.

References

  1. Jackson J, Jambrina E, Li J, Marston H, Menzies F, Phillips K, et al. Targeting the synapse in Alzheimer’s disease. Front Neurosci. 2019;13:735.

    Article  Google Scholar 

  2. Nguyen M, Krainc D. LRRK2 phosphorylation of auxilin mediates synaptic defects in dopaminergic neurons from patients with Parkinson’s disease. Proc Natl Acad Sci USA. 2018;115:5576–81.

    Article  CAS  Google Scholar 

  3. Morimura N, Yasuda H, Yamaguchi K, Katayama KI, Hatayama M, Tomioka NH, et al. Autism-like behaviours and enhanced memory formation and synaptic plasticity in Lrfn2/SALM1-deficient mice. Nat Commun. 2017;8:15800.

    Article  CAS  Google Scholar 

  4. Südhof TC. Towards an understanding of synapse formation. Neuron. 2018;100:276–93.

    Article  Google Scholar 

  5. Petanjek Z, Judaš M, Šimic G, Rasin MR, Uylings HBM, Rakic P, et al. Extraordinary neoteny of synaptic spines in the human prefrontal cortex. Proc Natl Acad Sci USA. 2011;108:13281–6.

    Article  CAS  Google Scholar 

  6. Huttenlocher PR, De Courten C, Garey LJ, Van, der Loos H. Synaptic development in human cerebral cortex. Int J Neurol. 1982;16–17:144–54.

    PubMed  Google Scholar 

  7. Bourgeois JP, Rakic P. Changes of synaptic density in the primary visual cortex of the macaque monkey from fetal to adult stage. J Neurosci. 1993;13:2801–20.

    Article  CAS  Google Scholar 

  8. Venkatesh HS, Morishita W, Geraghty AC, Silverbush D, Gillespie SM, Arzt M, et al. Electrical and synaptic integration of glioma into neural circuits. Nature. 2019;573:539–45.

    Article  CAS  Google Scholar 

  9. Venkataramani V, Tanev DI, Strahle C, Studier-Fischer A, Fankhauser L, Kessler T, et al. Glutamatergic synaptic input to glioma cells drives brain tumour progression. Nature. 2019;573:532–8.

    Article  CAS  Google Scholar 

  10. Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, et al. Identification of human brain tumour initiating cells. Nature. 2004;432:396–401.

    Article  CAS  Google Scholar 

  11. Daou MC, Smith TW, Litofsky NS, Hsieh CC, Ross AH. Doublecortin is preferentially expressed in invasive human brain tumors. Acta Neuropathol. 2005;110:472–80.

    Article  CAS  Google Scholar 

  12. Brehar FM, Gafencu AV, Trusca VG, Fuior EV, Arsene D, Amaireh M, et al. Preferential association of lissencephaly-1 gene expression with CD133+ glioblastoma cells. J Cancer. 2017;8:1284–91.

    Article  Google Scholar 

  13. Ortensi B, Setti M, Osti D, Pelicci G. Cancer stem cell contribution to glioblastoma invasiveness. Stem Cell Res Ther. 2013;4:18.

    Article  CAS  Google Scholar 

  14. Venkatesh HS, Johung TB, Caretti V, Noll A, Tang Y, Nagaraja S, et al. Neuronal activity promotes glioma growth through neuroligin-3 secretion. Cell. 2015;161:803–16.

    Article  CAS  Google Scholar 

  15. Venkatesh HS, Tam LT, Woo PJ, Lennon J, Nagaraja S, Gillespie SM, et al. Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma. Nature. 2017;549:533–7.

    Article  Google Scholar 

  16. Singh SK, Clarke ID, Hide T, Dirks PB. Cancer stem cells in nervous system tumors. Oncogene. 2004;23:7267–73.

    Article  CAS  Google Scholar 

  17. Diamandis P, Wildenhain J, Clarke ID, Sacher AG, Graham J, Bellows DS, et al. Chemical genetics reveals a complex functional ground state of neural stem cells. Nat Chem Biol. 2007;3:268–73.

    Article  CAS  Google Scholar 

  18. Diamandis P, Sacher AG, Tyers M, Dirks PB. New drugs for brain tumors? Insights from chemical probing of neural stem cells. Med Hypotheses. 2009;72:683–7.

    Article  CAS  Google Scholar 

  19. Cavalli FMG, Remke M, Rampasek L, Peacock J, Shih DJH, Luu B, et al. Intertumoral heterogeneity within medulloblastoma subgroups. Cancer Cell. 2017;31:737–754.e6.

    Article  CAS  Google Scholar 

  20. Ribatti D. The discovery of the placental growth factor and its role in angiogenesis: a historical review. Angiogenesis. 2008;11:215–21.

    Article  CAS  Google Scholar 

  21. Li Y, Muffat J, Omer A, Bosch I, Lancaster MA, Sur M, et al. Induction of expansion and folding in human cerebral organoids. Cell Stem Cell. 2017;20:385–396.e3.

    Article  Google Scholar 

  22. Weiland A, Wang Y, Wu W, Lan X, Han X, Li Q, et al. Ferroptosis and its role in diverse brain diseases. Mol Neurobiol. 2019;56:4880–93.

    Article  CAS  Google Scholar 

  23. Hambright WS, Fonseca RS, Chen L, Na R, Ran Q. Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain neurons promotes cognitive impairment and neurodegeneration. Redox Biol. 2017;12:8–17.

    Article  CAS  Google Scholar 

  24. Li Q, Han X, Lan X, Gao Y, Wan J, Durham F, et al. Inhibition of neuronal ferroptosis protects hemorrhagic brain. JCI Insight. 2017;2:e90777.

    Article  Google Scholar 

  25. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–72.

    Article  CAS  Google Scholar 

  26. Seano G, Primo L. Podosomes and invadopodia: tools to breach vascular basement membrane. Cell Cycle. 2015;14:1370–4.

    Article  CAS  Google Scholar 

  27. Murphy DA, Courtneidge SA. The ‘ins’ and ‘outs’ of podosomes and invadopodia: characteristics, formation and function. Nat Rev Mol Cell Biol. 2011;12:413–26.

    Article  CAS  Google Scholar 

  28. Sheng M, Kim E. The postsynaptic organization of synapses. Cold Spring Harb Perspect Biol. 2011;3:a005678.

    Article  Google Scholar 

  29. Südhof TC. The presynaptic active zone. Neuron 2012;75:11–25.

    Article  Google Scholar 

  30. Chubykin AA, Liu X, Comoletti D, Tsigelny I, Taylor P, Südhof TC. Dissection of synapse induction by neuroligins: effect of a neuroligin mutation associated with autism. J Biol Chem. 2005;280:22365–74.

    Article  CAS  Google Scholar 

  31. Verhage M, Maia AS, Plomp JJ, Brussaard AB, Heeroma JH, Vermeer H, et al. Synaptic assembly of the brain in the absence of neurotransmitter secretion. Science. 2000;287:864–9.

    Article  CAS  Google Scholar 

  32. Sando R, Bushong E, Zhu Y, Huang M, Considine C, Phan S, et al. Assembly of excitatory synapses in the absence of glutamatergic neurotransmission. Neuron. 2017;94:312–321.e3.

    Article  CAS  Google Scholar 

  33. Sigler A, Oh WC, Imig C, Altas B, Kawabe H, Cooper BH, et al. Formation and maintenance of functional spines in the absence of presynaptic glutamate release. Neuron. 2017;94:304–311.e4.

    Article  CAS  Google Scholar 

  34. Zhou Y, Hu P, Jiang J. Metabolite characterization of a novel sedative drug, remimazolam in human plasma and urine using ultra high-performance liquid chromatography coupled with synapt high-definition mass spectrometry. J Pharm Biomed Anal. 2017;137:78–83.

    Article  CAS  Google Scholar 

  35. Saunders NR, Dziegielewska KM, Møllgård K, Habgood MD. Physiology and molecular biology of barrier mechanisms in the fetal and neonatal brain. J Physiol. 2018;596:5723–56.

    Article  CAS  Google Scholar 

  36. Zeisel A, Hochgerner H, Lönnerberg P, Johnsson A, Memic F, van der Zwan J, et al. Molecular architecture of the mouse nervous system. Cell. 2018;174:999–1014.e22.

    Article  CAS  Google Scholar 

  37. Djuric U, Rodrigues DC, Batruch I, Ellis J, Shannon P, Diamandis P. Spatiotemporal proteomic profiling of human cerebral development. Mol Cell Proteom. 2017;16:1548–62.

    Article  CAS  Google Scholar 

  38. Djuric U, Lam KHB, Kao J, Batruch I, Jevtic S, Papaioannou M-D, et al. Defining protein pattern differences among molecular subtypes of diffuse gliomas using mass spectrometry. Mol Cell Proteomics. 2019:2029–43.

  39. Grenier K, Kao J, Diamandis P. Three-dimensional modeling of human neurodegeneration: brain organoids coming of age. Mol Psychiatry. 2019; 25:254–74.

    Article  Google Scholar 

  40. Lim-Fat MJ, Wen PY. Glioma progression through synaptic activity. Nat Rev Neurol. 2020;16:6–7.

    Article  Google Scholar 

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Acknowledgements

UD received stipend support from the Laboratory Medicine and Pathobiology Program at the University of Toronto and a Canadian Cancer Society Innovation Grant. PD receives funding support from the Princess Margaret Cancer Foundation, Ontario Institute for Cancer Research, Canadian Cancer Society Innovation Fund and The Terry Fox New Investigator Awards Program. We thank Dr Vuk Stambolic for helpful discussions.

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Authors and Affiliations

  1. Princess Margaret Cancer Centre, 101 College Street, Toronto, ON, M5G 1L7, Canada

    Jessica Malcolm, Clare Fiala, Ugljesa Djuric & Phedias Diamandis

  2. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, M5S 1A8, Canada

    Ugljesa Djuric & Phedias Diamandis

  3. Laboratory Medicine Program, University Health Network, 200 Elizabeth Street, Toronto, ON, Toronto, ON, M5G 2C4, Canada

    Phedias Diamandis

  4. Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada

    Phedias Diamandis

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Correspondence to Phedias Diamandis.

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Malcolm, J., Fiala, C., Djuric, U. et al. Can gliomas provide insights into promoting synaptogenesis?. Mol Psychiatry 25, 1920–1925 (2020). https://doi.org/10.1038/s41380-020-0795-4

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