Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Acta Neuropathologica
Published in: Acta Neuropathologica 1/2017

01-01-2017 | Original Paper

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

Authors: Sheng-Han Kuo, 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

Published in: Acta Neuropathologica | Issue 1/2017

Login to get access

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.
Literature
1.
Apps R, Hawkes R (2009) Cerebellar cortical organization: a one-map hypothesis. Nat Rev Neurosci 10:670–681CrossRefPubMed
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 136:3051–3061CrossRefPubMedPubMedCentral
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 31:12778–12789CrossRefPubMedPubMedCentral
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 11:287–290CrossRefPubMedPubMedCentral
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 112:389–404CrossRefPubMedPubMedCentral
6.
Braak H, Braak E (1997) Diagnostic criteria for neuropathologic assessment of Alzheimer’s disease. Neurobiol Aging 18:S85–S88CrossRefPubMed
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 64:1404–1410CrossRefPubMed
8.
9.
Cesa R, Strata P (2005) Axonal and synaptic remodeling in the mature cerebellar cortex. Prog Brain Res 148:45–56CrossRefPubMed
10.
Cesa R, Strata P (2009) Axonal competition in the synaptic wiring of the cerebellar cortex during development and in the mature cerebellum. Neuroscience 162:624–632CrossRefPubMed
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) 3
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 31:393–401CrossRefPubMed
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 33:5806–5820CrossRefPubMedPubMedCentral
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) 182:268–296CrossRef
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 69:262–271CrossRefPubMedPubMedCentral
16.
17.
Fox CA, Barnard JW (1957) A quantitative study of the Purkinje cell dendritic branchlets and their relationship to afferent fibres. J Anat 91:299–313PubMedPubMedCentral
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 31:247–260CrossRefPubMed
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 22:890–903CrossRefPubMed
20.
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 13:55–73CrossRefPubMed
22.
Handforth A (2012) Harmaline tremor: underlying mechanisms in a potential animal model of essential tremor. Tremor Other Hyperkinet Mov (N Y) 2
23.
Helmich RC, Toni I, Deuschl G, Bloem BR (2013) The pathophysiology of essential tremor and Parkinson’s tremor. Curr Neurol Neurosci Rep 13:378CrossRefPubMed
24.
Ito M, Yamaguchi K, Nagao S, Yamazaki T (2014) Long-term depression as a model of cerebellar plasticity. Prog Brain Res 210:1–30CrossRefPubMed
25.
26.
27.
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)
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 125:879–889CrossRefPubMedPubMedCentral
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 82:1038–1040CrossRefPubMed
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 137:3149–3159CrossRefPubMedPubMedCentral
32.
33.
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 28:779–786CrossRefPubMedPubMedCentral
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 28:1854–1859CrossRefPubMed
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 72:8–17CrossRef
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 137:3142–3148CrossRefPubMedPubMedCentral
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 31:119–126CrossRefPubMedPubMedCentral
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 119:375–377CrossRefPubMedPubMedCentral
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 130:3297–3307CrossRefPubMed
41.
Louis RJ, Lin CY, Faust PL, Koeppen AH, Kuo SH (2015) Climbing fiber synaptic changes correlate with clinical features in essential tremor. Neurology 84:2284–2286CrossRefPubMedPubMedCentral
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 97:2590–2604CrossRefPubMed
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 65:1863–1872
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–S94CrossRefPubMed
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 3:1023–1029
46.
Palay SL, Chan-Palay V (1974) Cerebellar cortex: cytology and organization. Springer, BerlinCrossRef
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 20:655–658CrossRefPubMedPubMedCentral
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 168:134–139CrossRefPubMed
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 18:626–628CrossRefPubMed
50.
Ramirez EP, Vonsattel JPG (2014) Neuropathologic changes of multiple system atrophy and diffuse lewy body disease. Semin Neurol 34:210–216CrossRefPubMed
51.
Seidel K, Siswanto S, Brunt ERP, den Dunnen W, Korf HW, Rüb U (2012) Brain pathology of spinocerebellar ataxias. Acta Neuropathol 124:1–21CrossRefPubMed
52.
Sharifi S, Nederveen AJ, Booij J, van Rootselaar A-F (2014) Neuroimaging essentials in essential tremor: a systematic review. Neuroimage Clin 5:217–231CrossRefPubMedPubMedCentral
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 31:14324–14334CrossRefPubMed
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 29:496–500CrossRefPubMed
55.
Thach WT (1967) Somatosensory receptive fields of single units in cat cerebellar cortex. J Neurophysiol 30:675–696PubMed
56.
Vonsattel JPG, Del Amaya MP, Keller CE (2008) Twenty-first century brain banking. Processing brains for research: the Columbia University methods. Acta Neuropathol 115:509–532CrossRefPubMed
57.
Watanabe M (2008) Molecular mechanisms governing competitive synaptic wiring in cerebellar Purkinje cells. Tohoku J Exp Med 214:175–190CrossRefPubMed
58.
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 24:2440–2448CrossRefPubMed
Metadata
Title
Climbing fiber-Purkinje cell synaptic pathology in tremor and cerebellar degenerative diseases
Authors
Sheng-Han Kuo
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
Publication date
01-01-2017
Publisher
Springer Berlin Heidelberg
Published in
Acta Neuropathologica / Issue 1/2017
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI
https://doi.org/10.1007/s00401-016-1626-1

Other articles of this Issue 1/2017

Acta Neuropathologica 1/2017 Go to the issue

Case Report

Deep sequencing reveals persistence of cell-associated mumps vaccine virus in chronic encephalitis

Original Paper

Mir-223 regulates the number and function of myeloid-derived suppressor cells in multiple sclerosis and experimental autoimmune encephalomyelitis

Original Paper

Pathological TDP-43 changes in Betz cells differ from those in bulbar and spinal α-motoneurons in sporadic amyotrophic lateral sclerosis

Original Paper

eEF2K inhibition blocks Aβ42 neurotoxicity by promoting an NRF2 antioxidant response

Consensus Paper

The current consensus on the clinical management of intracranial ependymoma and its distinct molecular variants

Correspondence

Tau neuropathology correlates with FDG-PET, but not AV-1451-PET, in progressive supranuclear palsy