Experimental parkinsonism in modeling striatal astrocyte damage

Abstract

Introduction. Astrocyte dysfunction is typical for many CNS pathologies, yet few experimental models of selective astrocyte damage, which would enable a fuller understanding of the role of astrocytes in the pathogenesis of neurodegenerative disorders, exist.

Study aim — to characterize the morphological brain changes with the administration of α-aminoadipic acid (L-AA), a glial toxin, into the rat striatum and to assess the effect of astrocyte dysfunction on motor activity in animals.

Materials and methods. Astrocyte damage was achieved by administering L-AA (100 μg in 5 μl) into the rats’ right striatum; the same volume of phosphate-buffered saline was injected into the left hemisphere as a control. On the third day after L-AA administration, motor impairment was assessed with normal and reduced dopaminergic neurotransmission; the latter was achieved with administration of the α-methyl-p-tyrosine, a tyrosine hydroxylase inhibitor. The immunohistochemical studies included assays for glial fibrillary acidic protein (GFAP), neuronal nuclear antigen (NeuN), and tyrosine hydroxylase.

Results. When dopamine synthesis was inhibited, damage to the striatal astrocytes, which was confirmed by immunohistochemistry, caused a reduction in motor activity in the open field test and an increase in the number of errors in the beam walking test. When dopaminergic transmission was reduced through the inhibition of tyrosine hydroxylase by α-methyl-p-tyrosine, the motor disturbances caused by astrocyte damage sustained and worsened.

Conclusion. The obtained data indicate the regulatory role of astroglia in the nigrostriatal system and emphasize the possible contribution of glial dysfunction to the motor disturbances in Parkinson’s disease.

About the authors

Alla V. Stavrovskaya

Research Center of Neurology, Moscow

Author for correspondence.
Email: platonova@neurology.ru
Russian Federation

Dmitry N. Voronkov

Research Center of Neurology, Moscow

Email: platonova@neurology.ru
Russian Federation

Artyem S. Ol’shansky

Research Center of Neurology, Moscow

Email: platonova@neurology.ru
Russian Federation

Anastasiya S. Gushchina

Research Center of Neurology, Moscow

Email: platonova@neurology.ru
Russian Federation

Nina G. Yamshchikova

Research Center of Neurology, Moscow

Email: platonova@neurology.ru
Russian Federation

References

  1. Verkhratsky A., Parpura V., Pekna M. et al. Glia in the pathogenesis of neurodegenerative diseases. Biochem Soc Trans 2014; 42: 1291–1301. doi: 10.1042/BST20140107. PMID: 25233406.
  2. Halliday G.M., Stevens C.H., Hons B. Glia: initiators and progressors of pathology in Parkinson’s disease. Mov Disord 2011; 26: 6–17. doi: 10.1002/mds.23455. PMID: 21322014.
  3. Banasr M., Duman R.S. Glial loss in the prefrontal cortex is sufficient to induce depressive-like behaviors. Biol Psychiatry 2008; 64: 863–870. doi: 10.1016/j.biopsych.2008.06.008. PMID: 18639237.
  4. Liddelow S.A., Barres B.A. Reactive astrocytes: production, function, and therapeutic potential. Immunity 2017; 46: 957–967. doi: 10.1016/j.immuni.2017.06.006. PMID: 28636962.
  5. Smiałowska M., Szewczyk B., Woźniak M. et al. Glial degeneration as a model of depression. Pharmacol Rep 2013; 65: 1572–1579. PMID: 24553005.
  6. Broe M. Astrocytic degeneration relates to the severity of disease in frontotemporal dementia. Brain 2004; 127: 2214–2220. doi: 10.1093/brain/awh250. PMID: 15282215.
  7. Olabarria M., Goldman J.E. Disorders of astrocytes: alexander disease as a model. Annu Rev Pathol Mech Dis 2017; 12: 131–152. doi: 10.1146/annurev-pathol-052016-100218. PMID: 28135564.
  8. Sofroniew M.V., Vinters H.V. Astrocytes: biology and pathology. Acta Neuropathol 2010; 119: 7–35. doi: 10.1007/s00401-009-0619-8. PMID: 20012068.
  9. Anderson M.A., Ao Y., Sofroniew M.V. Heterogeneity of reactive astrocytes. Neurosci Lett 2014; 565: 23–29. doi: 10.1016/j.neulet.2013.12.030. PMID: 24361547.
  10. Zhao Y., Keshiya S., Atashrazm F. et al. Nigrostriatal pathology with reduced astrocytes in LRRK2 S910/S935 phosphorylation deficient knockin mice. Neurobiol Dis 2018; 120: 76–87. doi: 10.1016/j.nbd.2018.09.003. PMID: 30194047.
  11. Mullett S.J., Di Maio R., Greenamyre J.T., Hinkle D.A. DJ-1 expression modulates astrocyte-mediated protection against neuronal oxidative stress. J Mol Neurosci 2013; 49: 507–511. doi: 10.1007/s12031-012-9904-4. PMID: 23065353.
  12. Kovacs G.G. Invited review: neuropathology of tauopathies: principles and practice. Neuropathol Appl Neurobiol 2015; 41: 3–23. doi: 10.1111/nan.12208. PMID: 25495175.
  13. Rostami J., Holmqvist S., Lindström V. et al. Human astrocytes transfer aggregated alpha-synuclein via tunneling nanotubes. J Neurosci 017; 37: 11835–11853. doi: 10.1523/JNEUROSCI.0983-17.2017. PMID: 29089438.
  14. Lindström V., Gustafsson G., Sanders L.H. et al. Extensive uptake of α-synuclein oligomers in astrocytes results in sustained intracellular deposits and mitochondrial damage. Mol Cell Neurosci 2017; 82: 143–156. doi: 10.1016/j.mcn.2017.04.009. PMID: 28450268.
  15. Cavaliere F., Cerf L., Dehay B. et al. In vitro α-synuclein neurotoxicity and spreading among neurons and astrocytes using Lewy body extracts from Parkinson disease brains. Neurobiol Dis 2017; 103: 101–112. doi: 10.1016/j.nbd.2017.04.011. PMID: 28411117.
  16. Proschel C., Stripay J.L., Shih C.H. et al. Delayed transplantation of precursor cell-derived astrocytes provides multiple benefits in a rat model of Parkinsons. EMBO Mol Med 2014; 6: 504–518. doi: 10.1002/emmm.201302878. PMID: 24477866.
  17. Nicaise C. Transplantation of stem cell-derived astrocytes for the treatment of amyotrophic lateral sclerosis and spinal cord injury. World J Stem Cells 2015; 7: 380. doi: 10.4252/wjsc.v7.i2.380. PMID: 25815122.
  18. Song J.J., Oh S.M., Kwon O.C. et al. Cografting astrocytes improves cell therapeutic outcomes in a Parkinson’s disease model. J Clin Invest 2017; 128: 463–482. doi: 10.1172/JCI93924. PMID: 29227284.
  19. Duan C.L., Liu C.W., Shen S.W. et al. Striatal astrocytes transdifferentiate into functional mature neurons following ischemic brain injury. Glia 2015; 63: 1660–1670. doi: 10.1002/glia.22837. PMID: 26031629.
  20. Emsley J.G., Macklis J.D. Astroglial heterogeneity closely reflects the neuronal-defined anatomy of the adult murine CNS. Neuron Glia Biol 2006; 2: 175. doi: 10.1017/S1740925X06000202. PMID: 17356684.
  21. Savtchouk I., Volterra A. Gliotransmission: beyond black-and-white. J Neurosci 2018; 38: 14–25. doi: 10.1523/JNEUROSCI.0017-17.2017. PMID: 29298905.
  22. Fiacco T.A., McCarthy K.D. Multiple lines of evidence indicate that gliotransmission does not occur under physiological conditions. J Neurosci 2018; 38: 3–13. doi: 10.1523/JNEUROSCI.0016-17.2017. PMID: 29298904.
  23. Jäkel S., Dimou L. Glial cells and their function in the adult brain: a journey through the history of their ablation. Front Cell Neurosci 2017; 11. doi: 10.3389/fncel.2017.00024. PMID: 28243193.
  24. Wilhelmsson U., Li L., Pekna M. et al. Absence of glial fibrillary acidic protein and vimentin prevents hypertrophy of astrocytic processes and improves post-traumatic regeneration. J Neurosci 2004; 24: 5016–5021. doi: 10.1523/JNEUROSCI.0820-04.2004. PMID: 15163694.
  25. Laterza C., Uoshima N., Tornero D. et al. Attenuation of reactive gliosis in stroke-injured mouse brain does not affect neurogenesis from grafted human iPSC-derived neural progenitors. PLoS One 2018; 13: e0192118. doi: 10.1371/journal.pone.0192118. PMID: 29401502.
  26. Willoughby J.O., Mackenzie L., Broberg M. et al. Fluorocitrate-mediated astroglial dysfunction causes seizures. J Neurosci Res 2003; 74: 160–166. doi: 10.1002/jnr.10743. PMID: 13130518.
  27. Khurgel M., Koo A.C., Ivy G.O. Selective ablation of astrocytes by intracerebral injections of α-aminoadipate. Glia 1996; 16: 351–358. doi: 10.1002/(SICI)1098-1136(199604)16:4<351::AID-GLIA7>3.0.CO;2-2. PMID: 8721675.
  28. Voloboueva L.A., Suh S.W., Swanson R.A., Giffard R.G. Inhibition of mitochondrial function in astrocytes: implications for neuroprotection. J Neurochem 2007; 102: 1383–1394. doi: 10.1111/j.1471-4159.2007.4634.x. PMID: 17488276.
  29. Kuter K., Olech Ł., Głowacka U. Prolonged dysfunction of astrocytes and activation of microglia accelerate degeneration of dopaminergic neurons in the rat substantia nigra and block compensation of early motor dysfunction induced by 6-OHDA. Mol Neurobiol 2018; 55: 3049–3066. doi: 10.1007/s12035-017-0529-z. PMID: 28466266.
  30. Fonnum F., Johnsen A., Hassel B. Use of fluorocitrate and fluoroacetate in the study of brain metabolism. Glia 1997; 21: 106–113. PMID: 9298853.
  31. Nishimura R.N., Santos D., Fu S.T., Dwyer B.E. Induction of cell death by L-alpha-aminoadipic acid exposure in cultured rat astrocytes: relationship to protein synthesis. Neurotoxicology 2000; 21: 313–320. PMID: 10894121.
  32. Lima A., Sardinha V.M., Oliveira A.F. et al. Astrocyte pathology in the prefrontal cortex impairs the cognitive function of rats. Mol Psychiatry 2014; 19: 834–841. doi: 10.1038/mp.2013.182. PMID: 24419043.
  33. Takada M., Hattori T. Fine structural changes in the rat brain after local injections of gliotoxin, alpha-aminoadipic acid. Histol Histopathol 1986; 1: 271–275. PMID: 2485166.
  34. Saffran B.N., Crutcher K.A. Putative gliotoxin, alpha-aminoadipic acid, fails to kill hippocampal astrocytes in vivo. Neurosci Lett 1987; 81: 215–220. PMID: 3696468.
  35. Chai H., Diaz-Castro B., Shigetomi E. et al. Neural Circuit-specialized astrocytes: transcriptomic, proteomic, morphological, and functional evidence. Neuron 2017; 95: 531–549.e9. doi: 10.1016/j.neuron.2017.06.029. PMID: 28712653.
  36. Dvorzhak A., Melnick I., Grantyn R. Astrocytes and presynaptic plasticity in the striatum: Evidence and unanswered questions. Brain Res Bull 2018; 136: 17–25. doi: 10.1016/j.brainresbull.2017.01.001. PMID: 28069435.
  37. Villalba R.M., Mathai A., Smith Y. Morphological changes of glutamatergic synapses in animal models of Parkinson’s disease. Front Neuroanat 2015; 9. doi: 10.3389/fnana.2015.00117. PMID: 26441550.
  38. Paxinos G., Watson Ch. The rat brain in stereotaxic coordinates. San Diego, 2006.
  39. Watanabe S., Fusa K., Takada K. et al. Effects of alpha-methyl-p-tyrosine on extracellular dopamine levels in the nucleus accumbens and the dorsal striatum of freely moving rats. J Oral Sci 2005; 47: 185–190. PMID: 16415562.
  40. Stavrovskaya A.V., Yamshchikova N.G., Ol’shanskiy A.S., Konovalova E.V., Illarioshkin S.N. [Transplantation of neuronal precursors derived from induced pluripotent stem cells into the striatum of rats with the toxin-induced model of Huntington’s disease] Annals of clinical and experimental neurology 2016; 10(4): 39–44.
  41. Jennings A., Rusakov D.A. Do astrocytes respond to dopamine? Opera Medica Physiol. 2016; 2: 34–43. doi: 10.20388/OMP2016.001.0017.

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Copyright (c) 2019 Stavrovskaya A.V., Voronkov D.N., Ol’shansky A.S., Gushchina A.S., Yamshchikova N.G.

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