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Acta Neuropathologica

, Volume 133, Issue 1, pp 121–138 | Cite as

Climbing fiber-Purkinje cell synaptic pathology in tremor and cerebellar degenerative diseases

  • Sheng-Han KuoEmail author
  • Chi-Ying Lin
  • Jie Wang
  • Peter A. Sims
  • Ming-Kai Pan
  • Jyun-you Liou
  • Danielle Lee
  • William J. Tate
  • Geoffrey C. Kelly
  • Elan D. Louis
  • Phyllis L. Faust
Original Paper

Abstract

Changes in climbing fiber-Purkinje cell (CF-PC) synaptic connections have been found in the essential tremor (ET) cerebellum, and these changes are correlated with tremor severity. Whether these postmortem changes are specific to ET remains to be investigated. We assessed CF-PC synaptic pathology in the postmortem cerebellum across a range of degenerative movement disorders [10 Parkinson’s disease (PD) cases, 10 multiple system atrophy (MSA) cases, 10 spinocerebellar ataxia type 1 (SCA1) cases, and 20 ET cases] and 25 controls. We observed differences in terms of CF pathological features across these disorders. Specifically, PD cases and ET cases both had more CFs extending into the parallel fiber (PF) territory, but ET cases had more complex branching and increased length of CFs in the PF territory along with decreased CF synaptic density compared to PD cases. MSA cases and SCA1 cases had the most severely reduced CF synaptic density and a marked paucity of CFs extending into the PF territory. Furthermore, CFs in a subset of MSA cases formed collateral branches parallel to the PC layer, a feature not seen in other diagnostic groups. Using unsupervised cluster analysis, the cases and controls could all be categorized into four clusters based on the CF pathology and features of PC pathology, including counts of PCs and their axonal torpedoes. ET cases and PD cases co-segregated into two clusters, whereas SCA1 cases and MSA cases formed another cluster, separate from the control cluster. Interestingly, the presence of resting tremor seemed to be the clinical feature that separated the cases into the two ET-PD clusters. In conclusion, our study demonstrates that these degenerative movement disorders seem to differ with respect to the pattern of CF synaptic pathology they exhibit. It remains to be determined how these differences contribute to the clinical presentations of these diseases.

Keywords

Essential tremor Parkinson’s disease Spinocerebellar ataxia Multiple system atrophy Climbing fiber Purkinje cell 

Notes

Acknowledgments

Dr. Arnulf H. Koeppen, Veterans Affairs Medical Center, Albany, New York, USA provided the rabbit polyclonal anti-VGluT2 antibody and the ten specimens of SCA1. We also thank the patients and families for the donation of brains and NYBB for processing of autopsy tissue.

Compliance with ethical standards

Funding

Dr. Kuo has received funding from the National Institutes of Health: NINDS #K08 NS083738 (principal investigator), and the Louis V. Gerstner Jr. Scholar Award, PD Foundation, and International ET Foundation, and NIEHS Pilot Grant ES009089 (principal investigator). Dr. Louis has received research support from the National Institutes of Health: NINDS #R01 NS042859 (principal investigator), NINDS #R01 NS39422 (principal investigator), NINDS #R01 NS086736 (principal investigator), NINDS #R01 NS073872 (principal investigator), NINDS #R01 NS085136 (principal investigator), and NINDS #R01 NS088257 (principal investigator). He has also received support from the Claire O’Neil ET Research Fund (Yale University). Dr. Faust has received funding from the National Institutes of Health: NINDS #R01 NS04289 (co-investigator), NINDS #R21 NS077094 (principal investigator), NINDS #R01 NS085136 (principal investigator), and NINDS #R01 NS088257 (principal investigator).

Conflict of interest

The authors report no conflicts of interest.

References

  1. 1.
    Apps R, Hawkes R (2009) Cerebellar cortical organization: a one-map hypothesis. Nat Rev Neurosci 10:670–681CrossRefPubMedGoogle Scholar
  2. 2.
    Babij R, Lee M, Cortes E, Vonsattel JPG, Faust PL, Louis ED (2013) Purkinje cell axonal anatomy: quantifying morphometric changes in essential tremor versus control brains. Brain 136:3051–3061CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Barnes JA, Ebner BA, Duvick LA, Gao W, Chen G, Orr HT, Ebner TJ (2011) Abnormalities in the climbing fiber-Purkinje cell circuitry contribute to neuronal dysfunction in ATXN1[82Q] mice. J Neurosci 31:12778–12789CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Bocchetta M, Cardoso MJ, Cash DM, Ourselin S, Warren JD, Rohrer JD (2016) Patterns of regional cerebellar atrophy in genetic frontotemporal dementia. Neuroimage Clin 11:287–290CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K (2006) Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol 112:389–404CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Braak H, Braak E (1997) Diagnostic criteria for neuropathologic assessment of Alzheimer’s disease. Neurobiol Aging 18:S85–S88CrossRefPubMedGoogle Scholar
  7. 7.
    Braak H, Rüb U, Jansen Steur ENH, Del Tredici K, de Vos RAI (2005) Cognitive status correlates with neuropathologic stage in Parkinson disease. Neurology 64:1404–1410CrossRefPubMedGoogle Scholar
  8. 8.
    Cesa R, Scelfo B, Strata P (2007) Activity-dependent presynaptic and postsynaptic structural plasticity in the mature cerebellum. J Neurosci 27:4603–4611. doi: 10.1523/JNEUROSCI.5617-06.2007 CrossRefPubMedGoogle Scholar
  9. 9.
    Cesa R, Strata P (2005) Axonal and synaptic remodeling in the mature cerebellar cortex. Prog Brain Res 148:45–56CrossRefPubMedGoogle Scholar
  10. 10.
    Cesa R, Strata P (2009) Axonal competition in the synaptic wiring of the cerebellar cortex during development and in the mature cerebellum. Neuroscience 162:624–632CrossRefPubMedGoogle Scholar
  11. 11.
    Cheng MM, Tang G, Kuo SH (2013) Harmaline-induced tremor in mice: videotape documentation and open questions about the model. Tremor Other Hyperkinet Mov (N Y) 3Google Scholar
  12. 12.
    Choe M, Cortes E, Vonsattel JPG, Kuo SH, Faust PL, Louis ED (2016) Purkinje cell loss in essential tremor: random sampling quantification and nearest neighbor analysis. Mov Disord 31:393–401CrossRefPubMedGoogle Scholar
  13. 13.
    Ebner BA, Ingram MA, Barnes JA, Duvick LA, Frisch JL, Clark HB, Zoghbi HY, Ebner TJ, Orr HT (2013) Purkinje cell ataxin-1 modulates climbing fiber synaptic input in developing and adult mouse cerebellum. J Neurosci 33:5806–5820CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Eccles JC, Llinás R, Sasaki K (1966) The excitatory synaptic action of climbing fibres on the Purkinje cells of the cerebellum. J Physiol (Lond) 182:268–296CrossRefGoogle Scholar
  15. 15.
    Erickson-Davis CR, Faust PL, Vonsattel JPG, Gupta S, Honig LS, Louis ED (2010) Hairy baskets associated with degenerative Purkinje cell changes in essential tremor. J Neuropathol Exp Neurol 69:262–271CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Fanciulli A, Wenning GK (2015) Multiple-system atrophy. NEJM 372:249–263CrossRefPubMedGoogle Scholar
  17. 17.
    Fox CA, Barnard JW (1957) A quantitative study of the Purkinje cell dendritic branchlets and their relationship to afferent fibres. J Anat 91:299–313PubMedPubMedCentralGoogle Scholar
  18. 18.
    Fremeau RT, Troyer MD, Pahner I, Nygaard GO, Tran CH, Reimer RJ, Bellocchio EE, Fortin D, Storm-Mathisen J, Edwards RH (2001) The expression of vesicular glutamate transporters defines two classes of excitatory synapse. Neuron 31:247–260CrossRefPubMedGoogle Scholar
  19. 19.
    Furrer SA, Waldherr SM, Mohanachandran MS, Baughn TD, Nguyen K-T, Sopher BL, Damian VA, Garden GA, La Spada AR (2013) Reduction of mutant ataxin-7 expression restores motor function and prevents cerebellar synaptic reorganization in a conditional mouse model of SCA7. Hum Mol Genet 22:890–903CrossRefPubMedGoogle Scholar
  20. 20.
    Grasselli G, Strata P (2013) Structural plasticity of climbing fibers and the growth-associated protein GAP-43. Front Neural Circuits 7:25CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Grodd W, Hülsmann E, Lotze M, Wildgruber D, Erb M (2001) Sensorimotor mapping of the human cerebellum: fMRI evidence of somatotopic organization. Hum Brain Mapp 13:55–73CrossRefPubMedGoogle Scholar
  22. 22.
    Handforth A (2012) Harmaline tremor: underlying mechanisms in a potential animal model of essential tremor. Tremor Other Hyperkinet Mov (N Y) 2Google Scholar
  23. 23.
    Helmich RC, Toni I, Deuschl G, Bloem BR (2013) The pathophysiology of essential tremor and Parkinson’s tremor. Curr Neurol Neurosci Rep 13:378CrossRefPubMedGoogle Scholar
  24. 24.
    Ito M, Yamaguchi K, Nagao S, Yamazaki T (2014) Long-term depression as a model of cerebellar plasticity. Prog Brain Res 210:1–30CrossRefPubMedGoogle Scholar
  25. 25.
    Koeppen AH (2005) The pathogenesis of spinocerebellar ataxia. Cerebellum 4:62–73CrossRefPubMedGoogle Scholar
  26. 26.
    Koeppen AH, Davis AN, Morral JA (2011) The cerebellar component of Friedreich’s ataxia. Acta Neuropathol 122:323–330CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Koeppen AH, Ramirez RL, Bjork ST, Bauer P, Feustel PJ (2013) The reciprocal cerebellar circuitry in human hereditary ataxia. Cerebellum. 12:493–503CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Kuo SH, Lin CY, Wang J, Liou JY, Pan MK, Louis RJ, Wu WP, Gutierrez J, Louis ED, Faust PL (2016) Deep brain stimulation and climbing fiber synaptic pathology in essential tremor. Ann Neurol (Epub ahead of print)Google Scholar
  29. 29.
    Kuo SH, Tang G, Louis ED, Ma K, Babji R, Balatbat M, Cortes E, Vonsattel J-PG, Yamamoto A, Sulzer D, Faust PL (2013) Lingo-1 expression is increased in essential tremor cerebellum and is present in the basket cell pinceau. Acta Neuropathol 125:879–889CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Kuo SH, Erickson-Davis C, Gillman A, Faust PL, Vonsattel JPG, Louis ED (2011) Increased number of heterotopic Purkinje cells in essential tremor. J Neurol Neurosurg Psychiatry 82:1038–1040CrossRefPubMedGoogle Scholar
  31. 31.
    Lin CY, Louis ED, Faust PL, Koeppen AH, Vonsattel JPG, Kuo SH (2014) Abnormal climbing fibre-Purkinje cell synaptic connections in the essential tremor cerebellum. Brain 137:3149–3159CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Louis ED (2009) Essential tremors: a family of neurodegenerative disorders? Arch Neurol 66:1202–1208CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Louis ED (2014) From neurons to neuron neighborhoods: the rewiring of the cerebellar cortex in essential tremor. Cerebellum 13:501–512CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Louis ED, Babij R, Cortes E, Vonsattel JPG, Faust PL (2013) The inferior olivary nucleus: a postmortem study of essential tremor cases versus controls. Mov Disord 28:779–786CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Louis ED, Babij R, Lee M, Cortes E, Vonsattel JPG (2013) Quantification of cerebellar hemispheric purkinje cell linear density: 32 ET cases versus 16 controls. Mov Disord 28:1854–1859CrossRefPubMedGoogle Scholar
  36. 36.
    Louis ED, Babij R, Ma K, Cortes E, Vonsattel JPG (2012) Essential tremor followed by progressive supranuclear palsy: postmortem reports of 11 patients. J Neuropathol Exp Neurol 72:8–17CrossRefGoogle Scholar
  37. 37.
    Louis ED, Lee M, Babij R, Ma K, Cortes E, Vonsattel JPG, Faust PL (2014) Reduced Purkinje cell dendritic arborization and loss of dendritic spines in essential tremor. Brain 137:3142–3148CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Louis ED, Mazzoni P, Ma KJ, Moskowitz CB, Lawton A, Garber A, Vonsattel JPG (2012) Essential tremor with ubiquitinated intranuclear inclusions and cerebellar degeneration. Clin Neuropathol 31:119–126CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Louis ED, Erickson-Davis C, Pahwa R, Lyons KE, Garber A, Moskowitz CB, Lawton A, Faust PL, Vonsattel JPG (2010) Essential tremor with ubiquitinated Purkinje cell intranuclear inclusions. Acta Neuropathol 119:375–377CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Louis ED, Faust PL, Vonsattel JPG, Honig LS, Rajput A, Robinson CA, Rajput A, Pahwa R, Lyons KE, Ross GW, Borden S, Moskowitz CB, Lawton A, Hernandez N (2007) Neuropathological changes in essential tremor: 33 cases compared with 21 controls. Brain 130:3297–3307CrossRefPubMedGoogle Scholar
  41. 41.
    Louis RJ, Lin CY, Faust PL, Koeppen AH, Kuo SH (2015) Climbing fiber synaptic changes correlate with clinical features in essential tremor. Neurology 84:2284–2286CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    McKay BE, Engbers JDT, Mehaffey WH, Gordon GRJ, Molineux ML, Bains JS, Turner RW (2007) Climbing fiber discharge regulates cerebellar functions by controlling the intrinsic characteristics of purkinje cell output. J Neurophysiol 97:2590–2604CrossRefPubMedGoogle Scholar
  43. 43.
    McKeith IG, Dickson DW, Lowe J, Emre M, O’Brien JT, Feldman H, Cummings J, Duda JE, Lippa C, Perry EK, Aarsland D, Arai H, Ballard CG, Boeve B, Burn DJ, Costa D, Del Ser T, Dubois B, Galasko D, Gauthier S, Goetz CG, Gomez-Tortosa E, Halliday G, Hansen LA, Hardy J, Iwatsubo T, Kalaria RN, Kaufer D, Kenny RA, Korczyn A, Kosaka K, Lee VMY, Lees A, Litvan I, Londos E, Lopez OL, Minoshima S, Mizuno Y, Molina JA, Mukaetova-Ladinska EB, Pasquier F, Perry RH, Schulz JB, Trojanowski JQ, Yamada M, Consortium on DLB (2005) Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 65:1863–1872Google Scholar
  44. 44.
    Mirra SS (1997) The CERAD neuropathology protocol and consensus recommendations for the postmortem diagnosis of Alzheimer’s disease: a commentary. Neurobiol Aging 18:S91–S94CrossRefPubMedGoogle Scholar
  45. 45.
    Nitschke MF, Kleinschmidt A, Wessel K, Frahm J (1996) Somatotopic motor representation in the human anterior cerebellum. A high-resolution functional MRI study. Brain 3:1023–1029Google Scholar
  46. 46.
    Palay SL, Chan-Palay V (1974) Cerebellar cortex: cytology and organization. Springer, BerlinCrossRefGoogle Scholar
  47. 47.
    Pan JJ, Lee M, Honig LS, Vonsattel JPG, Faust PL, Louis ED (2014) Alzheimer’s-related changes in non-demented essential tremor patients vs. controls: links between tau and tremor? Parkinsonism Relat Disord 20:655–658CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Pool M, Thiemann J, Bar-Or A, Fournier AE (2008) NeuriteTracer: a novel ImageJ plugin for automated quantification of neurite outgrowth. J Neurosci Methods 168:134–139CrossRefPubMedGoogle Scholar
  49. 49.
    Rajput AH, Robinson CA, Rajput ML, Robinson SL, Rajput A (2012) Essential tremor is not dependent upon cerebellar Purkinje cell loss. Parkinsonism Relat Disord 18:626–628CrossRefPubMedGoogle Scholar
  50. 50.
    Ramirez EP, Vonsattel JPG (2014) Neuropathologic changes of multiple system atrophy and diffuse lewy body disease. Semin Neurol 34:210–216CrossRefPubMedGoogle Scholar
  51. 51.
    Seidel K, Siswanto S, Brunt ERP, den Dunnen W, Korf HW, Rüb U (2012) Brain pathology of spinocerebellar ataxias. Acta Neuropathol 124:1–21CrossRefPubMedGoogle Scholar
  52. 52.
    Sharifi S, Nederveen AJ, Booij J, van Rootselaar A-F (2014) Neuroimaging essentials in essential tremor: a systematic review. Neuroimage Clin 5:217–231CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Shuvaev AN, Horiuchi H, Seki T, Goenawan H, Irie T, Iizuka A, Sakai N, Hirai H (2011) Mutant PKCγ in spinocerebellar ataxia type 14 disrupts synapse elimination and long-term depression in Purkinje cells in vivo. J Neurosci 31:14324–14334CrossRefPubMedGoogle Scholar
  54. 54.
    Symanski C, Shill HA, Dugger B, Hentz JG, Adler CH, Jacobson SA, Driver-Dunckley E, Beach TG (2014) Essential tremor is not associated with cerebellar Purkinje cell loss. Mov Disord 29:496–500CrossRefPubMedGoogle Scholar
  55. 55.
    Thach WT (1967) Somatosensory receptive fields of single units in cat cerebellar cortex. J Neurophysiol 30:675–696PubMedGoogle Scholar
  56. 56.
    Vonsattel JPG, Del Amaya MP, Keller CE (2008) Twenty-first century brain banking. Processing brains for research: the Columbia University methods. Acta Neuropathol 115:509–532CrossRefPubMedGoogle Scholar
  57. 57.
    Watanabe M (2008) Molecular mechanisms governing competitive synaptic wiring in cerebellar Purkinje cells. Tohoku J Exp Med 214:175–190CrossRefPubMedGoogle Scholar
  58. 58.
    Wu T, Hallett M (2013) The cerebellum in Parkinson’s disease. Brain 136:696–709CrossRefPubMedGoogle Scholar
  59. 59.
    Yoshida T, Katoh A, Ohtsuki G, Mishina M, Hirano T (2004) Oscillating Purkinje neuron activity causing involuntary eye movement in a mutant mouse deficient in the glutamate receptor delta2 subunit. J Neurosci 24:2440–2448CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Sheng-Han Kuo
    • 1
    Email author
  • Chi-Ying Lin
    • 1
    • 2
  • Jie Wang
    • 1
    • 3
  • Peter A. Sims
    • 4
  • Ming-Kai Pan
    • 1
    • 5
  • Jyun-you Liou
    • 6
  • Danielle Lee
    • 1
  • William J. Tate
    • 7
  • Geoffrey C. Kelly
    • 7
  • Elan D. Louis
    • 8
    • 9
  • Phyllis L. Faust
    • 7
  1. 1.Department of Neurology, College of Physicians and SurgeonsColumbia UniversityNew YorkUSA
  2. 2.Department of NeurologyIcahn School of Medicine at Mount SinaiNew YorkUSA
  3. 3.Department of Basic and Community Nursing, School of NursingNanjing Medical UniversityNanjingChina
  4. 4.Departments of System Biology and Biochemistry and Molecular BiophysicsColumbia UniversityNew YorkUSA
  5. 5.Department of Medical ResearchNational Taiwan University HospitalTaipeiTaiwan
  6. 6.Department of Physiology and Cellular BiophysicsColumbia UniversityNew YorkUSA
  7. 7.Department of Pathology and Cell BiologyColumbia University Medical Center and the New York Presbyterian HospitalNew YorkUSA
  8. 8.Department of Neurology, Yale School of MedicineYale UniversityNew HavenUSA
  9. 9.Department of Chronic Disease Epidemiology, Yale School of Public HealthYale UniversityNew HavenUSA

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