The Potential Role of Nonneuronal Cells in the Deep Brain Stimulation Mechanism

What Are Glia? What Are Their Functions? Could They Be Players in Deep Brain Stimulation?
  • Vinata Vedam-Mai
  • Michael S. Okun
  • Elly M. Hol


Deep brain stimulation (DBS) is the surgical therapy of choice for a variety of treatment-resistant movement disorders, and many neuropsychiatric disorders. However, the mode of action of DBS is still unclear. It is unknown which neural cell types in the complex brain circuitry are involved in the workings of DBS, and how high-frequency stimulation of specific cell types may lead to the alleviation of a patient’s clinical symptoms. Although the existing theories of the working of DBS rely mostly on neurons, it is likely that other cell types could be involved. It is known that glia are heavily involved in synaptic communication through the formation of the tripartite synapse. Recent evidence indicates that DBS can result in direct activation of glial cells to release gliotransmitters. This in turn can have an effect on the tripartite synapse, as well as on downstream network activity. In this chapter we focus on reviewing the effects of DBS on nonneuronal cells, and speculate on the potential role of DBS-mediated glial activation.


Deep Brain Stimulation Essential Tremor Deep Brain Stimulation Electrode Neurogenic Niche Neural Network Activity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Allaman I, Belanger M, Magistretti PJ (2011) Astrocyte-neuron metabolic relationships: for better and for worse. Trends Neurosci 34:76–87. doi: 10.1016/j.tins.2010.12.001 Google Scholar
  2. Bekar LK et al (2005) Complex expression and localization of inactivating Kv channels in cultured hippocampal astrocytes. J Neurophysiol 93:1699–1709. doi: 10.1152/jn.00850.2004 Google Scholar
  3. Bekar L et al (2008) Adenosine is crucial for deep brain stimulation-mediated attenuation of tremor. Nat Med 14:75–80. doi: 10.1038/nm1693 Google Scholar
  4. Bergles DE, RobertsJD, Somogyi P, Jahr CE (2000) Glutamatergic synapses on oligodendrocyte precursor cells in the hippocampus. Nature 405:187–191. doi: 10.1038/35012083
  5. Beurrier C, Bioulac B, Audin J, Hammond C (2001) High-frequency stimulation produces a transient blockade of voltage-gated currents in subthalamic neurons. J Neurophysiol 85:1351–1356PubMedGoogle Scholar
  6. Bezzi P, Volterra A (2001) A neuron-glia signalling network in the active brain. Curr Opin Neurobiol 11:387–394PubMedCrossRefGoogle Scholar
  7. Bezzi P, Domercq M, Vesce S, Volterra A (2001) Neuron-astrocyte cross-talk during synaptic transmission: physiological and neuropathological implications. Prog Brain Res 132:255–265. doi: 10.1016/S0079-6123(01)32081-2 Google Scholar
  8. Boraud T, Bezard E, Bioulac B, Gross C (1996) High frequency stimulation of the internal globus pallidus (GPi) simultaneously improves parkinsonian symptoms and reduces the firing frequency of GPi neurons in the MPTP-treated monkey. Neurosci Lett 215:17–20PubMedCrossRefGoogle Scholar
  9. Bowser DN, Khakh BS (2004) ATP excites interneurons and astrocytes to increase synaptic inhibition in neuronal networks. J Neurosci 24:8606–8620. doi: 10.1523/JNEUROSCI.2660-04.2004 Google Scholar
  10. Buffo A et al (2008) Origin and progeny of reactive gliosis: a source of multipotent cells in the injured brain. Proc Natl Acad Sci U S A 105:3581–3586. doi: 10.1073/pnas.0709002105 Google Scholar
  11. Chang SY, Shon YM, Agnesi F, Lee KH (2006) Microthalamotomy effect during deep brain stimulation: potential involvement of adenosine and glutamate efflux. Conf Proc IEEE Eng Med Biol Soc 2009:3294–3297. doi: 10.1109/IEMBS.2009.5333735
  12. Charles A (2005) Reaching out beyond the synapse: glial intercellular waves coordinate metabolism. Sci STKE 2005:pe6. doi: 10.1126/stke.2702005pe6
  13. Dani JW, Chernjavsky A, Smith SJ (1992) Neuronal activity triggers calcium waves in hippocampal astrocyte networks. Neuron 8:429–440PubMedCrossRefGoogle Scholar
  14. Dawson MR, Polito A, Levine JM, Reynolds R (2003) NG2-expressing glial progenitor cells: an abundant and widespread population of cycling cells in the adult rat CNS. Mol Cell Neurosci 24:476–488PubMedCrossRefGoogle Scholar
  15. Dostrovsky JO et al (2000) Microstimulation-induced inhibition of neuronal firing in human globus pallidus. J Neurophysiol 84:570–574PubMedGoogle Scholar
  16. Eroglu C, Barres BA (2010) Regulation of synaptic connectivity by glia. Nature 468:223–231. doi: 10.1038/nature09612 Google Scholar
  17. Fukumitsu N et al (2005) Adenosine A1 receptor mapping of the human brain by PET with 8-dicyclopropylmethyl-1-11C-methyl-3-propylxanthine. J Nucl Med 46:32–37PubMedGoogle Scholar
  18. Gallo V, Patneau DK, Mayer ML, Vaccarino FM (1994) Excitatory amino acid receptors in glial progenitor cells: molecular and functional properties. Glia 11:94–101. doi: 10.1002/glia.440110204 Google Scholar
  19. Giaume C, Koulakoff A, Roux L, Holcman D, Rouach N (2010) Astroglial networks: a step further in neuroglial and gliovascular interactions. Nat Rev Neurosci 11:87–99. doi: 10.1038/nrn2757 Google Scholar
  20. Gradinaru V, Mogri M, Thompson KR, Henderson JM, Deisseroth K (2009) Optical deconstruction of parkinsonian neural circuitry. Science 324:354–359. doi: 10.1126/science.1167093 Google Scholar
  21. Greenberg BD et al (2006) Three-year outcomes in deep brain stimulation for highly resistant obsessive-compulsive disorder. Neuropsychopharmacology 31:2384–2393. doi: 10.1038/sj.npp.1301165 Google Scholar
  22. Grosche J et al (1999) Microdomains for neuron-glia interaction: parallel fiber signaling to Bergmann glial cells. Nat Neurosci 2:139–143. doi: 10.1038/5692 Google Scholar
  23. Halassa MM, Haydon PG (2010) Integrated brain circuits: astrocytic networks modulate neuronal activity and behavior. Annu Rev Physiol 72:335–355. doi: 10.1146/annurev-physiol-021909-135843
  24. Hamann M, Rossi DJ, Mohr C, Andrade AL, Attwell D (2005) The electrical response of cerebellar Purkinje neurons to simulated ischaemia. Brain 128:2408–2420. doi: 10.1093/brain/awh619 Google Scholar
  25. Haydon PG, Carmignoto G (2006) Astrocyte control of synaptic transmission and neurovascular coupling. Physiol Rev 86:1009–1031. doi: 10.1152/physrev.00049.2005 Google Scholar
  26. Jacobson KA, Gao ZG (2006) Adenosine receptors as therapeutic targets. Nat Rev Drug Discov 5:247–264. doi: 10.1038/nrd1983 Google Scholar
  27. Kimura K, Yanagida Y, Haruyama T, Kobatake E, Aizawa M (1998) Gene expression in the electrically stimulated differentiation of PC12 cells. J Biotechnol 63:55–65PubMedCrossRefGoogle Scholar
  28. Kirchhoff F, Kettenmann H (1992) GABA triggers a [Ca2+]i increase in murine precursor cells of the oligodendrocyte lineage. Eur J Neurosci 4:1049–1058PubMedCrossRefGoogle Scholar
  29. Knutson P, Ghiani CA, Zhou JM, Gallo V, McBain CJ (1997) K+ channel expression and cell proliferation are regulated by intracellular sodium and membrane depolarization in oligodendrocyte progenitor cells. J Neurosci 17:2669–2682PubMedGoogle Scholar
  30. Kojima J et al (1992) Electrically promoted protein production by mammalian cells cultured on the electrode surface. Biotechnol Bioeng 39:27–32. doi: 10.1002/bit.260390106 Google Scholar
  31. Koyama S, Haruyama T, Kobatake E, Aizawa M (1997) Electrically induced NGF production by astroglial cells. Nat Biotechnol 15:164–166. doi: 10.1038/nbt0297-164 Google Scholar
  32. Kozlov AS, AnguloMC, Audinat E, Charpak S (2006) Target cell-specific modulation of neuronal activity by astrocytes. Proc Natl Acad Sci USA 103:10058–10063. doi: 10.1073/pnas.0603741103
  33. Kulik A, Haentzsch A, Luckermann M, Reichelt W, Ballanyi K (1999) Neuron-glia signaling via alpha(1) adrenoceptor-mediated Ca(2 +) release in Bergmann glial cells in situ. J Neurosci 19:8401–8408PubMedGoogle Scholar
  34. Lin SC, Bergles DE (2004) Synaptic signaling between neurons and glia. Glia 47:290–298. doi: 10.1002/glia.20060 Google Scholar
  35. Lujan JL, Chaturvedi A, McIntyre CC (2008) Tracking the mechanisms of deep brain stimulation for neuropsychiatric disorders. Front Biosci 13:5892–5904PubMedCrossRefGoogle Scholar
  36. Matsunaga K, Uozumi T, Hashimoto T, Tsuji S (2001) Cerebellar stimulation in acute cerebellar ataxia. Clin Neurophysiol 112:619–622PubMedCrossRefGoogle Scholar
  37. Mayberg HS et al (2005) Deep brain stimulation for treatment-resistant depression. Neuron 45:651–660. doi: 10.1016/j.neuron.2005.02.014 Google Scholar
  38. Nedergaard M (1994) Direct signaling from astrocytes to neurons in cultures of mammalian brain cells. Science 263:1768–1771PubMedCrossRefGoogle Scholar
  39. Newman EA (2003) Glial cell inhibition of neurons by release of ATP. J Neurosci 23:1659–1666PubMedGoogle Scholar
  40. Newman EA, Zahs KR (1997) Calcium waves in retinal glial cells. Science 275:844–847PubMedCrossRefGoogle Scholar
  41. Nishiyama A, Komitova M, Suzuki R, Zhu X (2009) Polydendrocytes (NG2 cells): multifunctional cells with lineage plasticity. Nat Rev Neurosci 10:9–22. doi: 10.1038/nrn2495 Google Scholar
  42. Oberheim NA, Wang X, Goldman S, Nedergaard M (2006) Astrocytic complexity distinguishes the human brain. Trends Neurosci 29:547–553. doi: 10.1016/j.tins.2006.08.004 Google Scholar
  43. Panatier A et al (2011) Astrocytes are endogenous regulators of basal transmission at central synapses. Cell. doi: 10.1016/j.cell.2011.07.022
  44. Papay R et al (2004) Mouse alpha1B-adrenergic receptor is expressed in neurons and NG2 oligodendrocytes. J Comp Neurol 478:1–10. doi: 10.1002/cne.20215 (2004)Google Scholar
  45. Paukert M, Bergles DE (2006) Synaptic communication between neurons and NG2+ cells. Curr Opin Neurobiol 16:515–521. doi: 10.1016/j.conb.2006.08.009 Google Scholar
  46. Perea G, Araque A (2005) Properties of synaptically evoked astrocyte calcium signal reveal synaptic information processing by astrocytes. J Neurosci 25:2192–2203. doi: 10.1523/JNEUROSCI.3965-04.2005 Google Scholar
  47. Perea G, Araque A (2005) Synaptic regulation of the astrocyte calcium signal. Journal of neural transmission 112:127–135. doi: 10.1007/s00702-004-0170-7 Google Scholar
  48. Rauch SL (2003) Neuroimaging and neurocircuitry models pertaining to the neurosurgical treatment of psychiatric disorders. Neurosurg Clin N Am 14:213–223, vii–viiiGoogle Scholar
  49. Rauch SL et al (2006) A functional neuroimaging investigation of deep brain stimulation in patients with obsessive-compulsive disorder. Journal of Neurosurgery 104:558–565. doi: 10.3171/jns.2006.104.4.558 Google Scholar
  50. Sakry D, Karram K, Trotter J (2011) Synapses between NG2 glia and neurons. J Anat 219:2–7. doi: 10.1111/j.1469-7580.2011.01359.x Google Scholar
  51. Schipke CG, Kettenmann H (2004) Astrocyte responses to neuronal activity. Glia 47:226–232. doi: 10.1002/glia.20029 Google Scholar
  52. Shah RS et al (2010) Deep brain stimulation: technology at the cutting edge. J Clin Neurol 6:167–182. doi: 10.3988/jcn.2010.6.4.167 Google Scholar
  53. Steiner B et al (2006) Enriched environment induces cellular plasticity in the adult substantia nigra and improves motor behavior function in the 6-OHDA rat model of Parkinson’s disease. Exp Neurol 199:291–300. doi: 10.1016/j.expneurol.2005.11.004 Google Scholar
  54. Steiner B et al (2008) Unilateral lesion of the subthalamic nucleus transiently provokes bilateral subacute glial cell proliferation in the adult rat substantia nigra. Neurosci Lett 430:103–108. doi: 10.1016/j.neulet.2007.10.045 Google Scholar
  55. Tawfik VL et al (2010) Deep brain stimulation results in local glutamate and adenosine release: investigation into the role of astrocytes. Neurosurgery 67:367–375. doi: 10.1227/01.NEU.0000371988.73620.4C Google Scholar
  56. Van Laere K et al (2006) Metabolic imaging of anterior capsular stimulation in refractory obsessive-compulsive disorder: a key role for the subgenual anterior cingulate and ventral striatum. J Nucl Med 47:740–747PubMedGoogle Scholar
  57. Vedam-Mai V et al (2011) Deep brain stimulation and the role of astrocytes. Mol Psychiatry. doi: 10.1038/mp.2011.61
  58. Velez-Fort M, Maldonado PP, Butt AM, Audinat E, Angulo MC (2010) Postnatal switch from synaptic to extrasynaptic transmission between interneurons and NG2 cells. J Neurosci 30:6921–6929. doi: 10.1523/JNEUROSCI.0238-10.2010 Google Scholar
  59. Vitek JL (2002) Mechanisms of deep brain stimulation: excitation or inhibition. Mov Disord 17(Suppl 3):S69–S72PubMedCrossRefGoogle Scholar
  60. Volterra A, Meldolesi J (2005) Astrocytes, from brain glue to communication elements: the revolution continues. Nat Rev Neurosci 6:626–640. doi: 10.1038/nrn1722 Google Scholar
  61. Wang DD, Bordey A (2008) The astrocyte odyssey. Progress in neurobiology 86:342–367. doi: 10.1016/j.pneurobio.2008.09.015
  62. Windels F et al (2000) Effects of high frequency stimulation of subthalamic nucleus on extracellular glutamate and GABA in substantia nigra and globus pallidus in the normal rat. Eur J Neurosci 12:4141–4146PubMedCrossRefGoogle Scholar
  63. Wu YR, Levy R, Ashby P, Tasker RR, Dostrovsky JO (2001) Does stimulation of the GPi control dyskinesia by activating inhibitory axons? Mov Disord 16:208–216PubMedCrossRefGoogle Scholar
  64. Yanagida Y, Mizuno A, Motegi T, Kobatake E, Aizawa M (2000) Electrically stimulated induction of hsp70 gene expression in mouse astroglia and fibroblast cells. J Biotechnol 79:53–61PubMedCrossRefGoogle Scholar
  65. Zahs KR, Newman EA (1997) Asymmetric gap junctional coupling between glial cells in the rat retina. Glia 20:10–22PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Vinata Vedam-Mai
    • 1
  • Michael S. Okun
    • 1
  • Elly M. Hol
    • 2
    • 3
  1. 1.Department of Neurology, Movement Disorders Center, McKnight Brain InstituteUniversity of Florida College of MedicineGainesvilleUSA
  2. 2.Netherlands Institute for NeuroscienceRoyal Netherlands Academy of Arts and SciencesAmsterdamThe Netherlands
  3. 3.Center for Neuroscience, Swammerdam Institute for Life SciencesUniversity of AmsterdamAmsterdamThe Netherlands

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