https://doi.org/10.4081/ejh.2024.3954
A candidate projective neuron type of the cerebellar cortex: the synarmotic neuron
Submitted: 29 December 2023
Accepted: 20 April 2024
Published: 15 May 2024
Accepted: 20 April 2024
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All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
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Previous studies on the granular layer of the cerebellar cortex have revealed a wide distribution of different subpopulations of less-known large neuron types, called “non-traditional large neurons”, which are distributed in three different zones of the granular layer. These neuron types are mainly involved in the formation of intrinsiccircuits inside the cerebellar cortex. A subpopulation of these neuron types is represented by the synarmotic neuron, which could play a projective role within the cerebellar circuitry. The synarmotic neuron cell body map within the internal zone of the granular layer or in the subjacent white substance. Furthermore, the axon crosses the granular layer and runs in the subcortical white substance, to reenter in an adjacent granular layer, associating two cortico-cerebellar regions of the same folium or of different folia, or could project to the intrinsic cerebellar nuclei. Therefore, along with the Purkinje neuron, the traditional projective neuron type of the cerebellar cortex, the synarmotic neuron is candidate to represent the second projective neuron type of the cerebellar cortex. Studies of chemical neuroanatomy evidenced a predominant inhibitory GABAergic nature of the synarmotic neuron, suggesting that it may mediate an inhibitory GABAergic output of cerebellar cortex within cortico-cortical interconnections or in projections towards intrinsic cerebellar nuclei. On this basis, the present minireview mainly focuses on the morphofunctional and neurochemical data of the synarmotic neuron, and explores its potential involvement in some forms of cerebellar ataxias.
Jansen J, Brodal A. [Das Kleinhirn] In: Bargman W, editor. [Handbuch der Mikroskopiscen Anatomie des Menschen].[Book in German]. Berlin, Springer; 1958. pp 91-149.
DOI: https://doi.org/10.1007/978-3-662-21749-8_3
Eccles JC, Ito M, Szentàgothai J. The cerebellum as a new neuronal machine. Springer, Berlin; 1967.
DOI: https://doi.org/10.1007/978-3-662-13147-3
Fox CA, Snider RS, The cerebellum. Amsterdam, Elsevier; 1967.
Mugnaini, E. The histology and cytology of the cerebellar cortex. In: Larsell O, Jansen J. editors. The comparative anatomy and histology of the cerebellum: the human cerebellum, cerebellar connections and cerebellar cortex. Minneapolis, Minnesota Press; 1972. pp 201-64.
Ito M. The cerebellum and neural control. New York, Raven Press; 1984.
Ito M. The cerebellum: brain for an implicit self. Upper Saddle River, FT Press: 2011.
Gabbott PL, Somogyi P, Stewart MG, Hamori J. GABA-immunoreactive neurons in the rat cerebellum: a light and electron microscope study. J Comp Neurol 1986;251:474-90.
DOI: https://doi.org/10.1002/cne.902510404
Flace P, Benagiano V, Virgintino D, Rizzi A. [L’immunocitochimica per GAD e GABA rivela elementi GABAergici della corteccia cerebellare di uomo].[in Italian] Proc. 7th Nat. Congr. Young Investigator of Neuroscience, Pisa; 2000; p. 10.
Benagiano V, Flace P, Virgintino D, Rizzi A, Roncali L, Ambrosi G. Immunolocalization of glutamic acid decarboxylase in postmortem human cerebellar cortex. A light microscopy study. Histochem Cell Biol 2000;114:191-5.
DOI: https://doi.org/10.1007/s004180000180
Clements JR, Monaghan PL, Beitz AJ. An ultrastructural description of glutamate-like immunoreactivity in the rat cerebellar cortex. Brain Res 1987;421:343-8.
DOI: https://doi.org/10.1016/0006-8993(87)91304-7
Ottersen OP, Laake JH, Storm-Mathisen J. Demonstration of releasable pool of glutamate in cerebellar mossy and parallel fibre terminals by means of light and electron microscopic immunohistochemistry. Arch Ital Biol 1990;128:111-25.
Braak E, Braak H. On three types of large nerve cells in the granular layer of the human cerebellar cortex. Anat Embryol
(Berl) 1983;166:67-86.
DOI: https://doi.org/10.1007/BF00317945
Mugnaini E, Floris A. Unipolar brush cell: a neglected neuron of the mammalian cerebellar cortex. J Comp Neurol 1994;339:174-80.
DOI: https://doi.org/10.1002/cne.903390203
Geurts FJ, Timmermans J, Shigemoto R, De Schutter E. Morphological and neurochemical differentiation of large granular layer interneurons in the adult rat cerebellum. Neuroscience 2001;104;499-512.
DOI: https://doi.org/10.1016/S0306-4522(01)00058-6
Geurts FJ, De Schutter E, Dieudonné S. Unraveling the cerebellar cortex: cytology and cellular physiology of large-sized interneurons in the granular layer. Cerebellum 2003;2:290-9.
DOI: https://doi.org/10.1080/14734220310011948
Flace P, Benagiano V, Lorusso L, Girolamo F, Rizzi A, Virgintino D, et al. Glutamic acid decarboxylase immunoreactive large neuron types in the granular layer of the human cerebellar cortex. Anat Embryol 2004;208:55-64.
DOI: https://doi.org/10.1007/s00429-003-0374-x
Ambrosi G, Flace P, Lorusso L, Girolamo F, Rizzi A, Bosco L, et al. Non-traditional large neuron in the granular layer of the cerebellar cortex. Eur J Histochem 2007;51:59-64.
Schilling K, Oberdick J, Rossi F, Baader SL. Besides Purkinje cells and granule neurons: an appraisal of the cell biology of the interneurons of the cerebellar cortex. Histochem Cell Biol 2008;130:601-15.
DOI: https://doi.org/10.1007/s00418-008-0483-y
Mugnaini E, Sekerkova G, Martina M. The unipolar brush cell a remarkable neuron finally receiving deserved attention. Brain Res Rev 2011;66:220-45.
DOI: https://doi.org/10.1016/j.brainresrev.2010.10.001
Jacobs B, Johnson NL, Wahl D, Schall M, Maseko BC, Lewandowski A, et al. Comparative neuronal morphology of the cerebellar cortex in afrotherians, carnivores, cetartiodactyls and primates. Front Neuroanat 2014;8:24.
DOI: https://doi.org/10.3389/fnana.2014.00069
Flace P. The neglected non-traditional large neuron types in the granular layer of the cerebellar cortex: Morphofunctional and neurochemical data. Ital J Anat Embryol 2017;122:225.
Flace P. New immunohistochemical data on the non-traditional large neuron types of the granular layer of the human cerebellar cortex. Proc. 65th Congr. Italian Embryological Group (GEI - SIBSC) - 38th Congr. Italian Society of Histochemistry (SII), Ancona, 2019; p. 14. Eur J Histochem 2019;63:3052.
Flace P. Neurochemical data on the non-traditional large neuron types of the granular layer of the human cerebellar cortex. Proc. 29th Nat Conf Italian Group for the Study of Neuromorphology (GISN), p. 2. Eur J Histochem 2020;64:3121.
Flace P, Milardi D, Basile GA, Gennarini G, Anastasi G. A light microscopy study on the neurotensiergic system in the human cerebellum. Proc. 28th Nat. Congr. Italian Group for the Study of Neuromorphology (GISN), Florence, 2018; p.16.
Flace P, Anastasi G, Milardi D, Basile GA, Quartarone A, Cacciola A. The human cerebellar dopaminergic system, its links to the midbrain dopaminergic nuclei and role in neurologic and psychiatric diseases. Neurol Sci 2019;40:S262.
Mugnaini E. GABAergic inhibition in the cerebellar system. In: Martin DL, Olsen RW, editors. GABA in the nervous system: the view at fifty years. Philadelphia, Lippincott; 2000. pp 383-407.
Altmann J, Bayer SA. Time of origin and distribution of a new cell type in rat cerebellar cortex. Exp Brain Res 1977;29:265-74.
DOI: https://doi.org/10.1007/BF00237046
Munoz DG. Monodendritic neurons: a cell type in the human cerebellar cortex identified by chromogranin A-like immunoreactivity. Brain Res 1990;528:335-8.
DOI: https://doi.org/10.1016/0006-8993(90)91678-A
Braak E, Braak H. The new monodendritic neuronal type within the adult human cerebellar granule cell layer shows calretinin-immunoreactivity. Neurosci Lett 1993;154:188-202.
DOI: https://doi.org/10.1016/0304-3940(93)90206-Z
Crook J, Hendrickson A, Robinson, FR. Co-localization of glycine and gaba immunoreactivity in interneurons in Macaca monkey cerebellar cortex. Neuroscience 2006;141:1951-9.
DOI: https://doi.org/10.1016/j.neuroscience.2006.05.012
Hirono M, Nagao S, Yanagawa Y, Konishi S. Monoaminergic modulation of GABAergic transmission onto cerebellar globular cells. Neuropharmacology 2017;118:79-89.
DOI: https://doi.org/10.1016/j.neuropharm.2017.03.011
Flace P, Milardi D, Cacciola A, Basile G. Multidisciplinary morphological approaches to the intrinsic human cerebellar dopaminergic system, its projection and clinical role. Ital J Anat Embryol 2018;123:91.
Flace P, Cacciola A, Milardi D, Basile GA, Anastasi G. Immunohistochemical and tractographic approaches on the human cerebellar dopaminergic system. Proc. 65th Congr. Italian Embryological Group (GEI - SIBSC) - 38th Congr. Italian Society of Histochemistry (SII), Ancona, 2019; p. 14. Eur J Histochem 2019;63:3052.
Flace P, Bizzoca A, Livrea P, Gennarini G. The synarmotic neuron. A candidate projective neuron type of the cerebellar cortex. Neurol Sci 2022;43:S432.
Flace P, Galletta D, Bizzoca A, Gennarini G, Livrea P. New immunohistochemical data on the cerebellar synarmotic neuron type. Proc. 28th Nat. Congr. Italian Group for the Study of Neuromorphology (GISN), Florence, 2018; p.16.
Golgi C. Sulla fina anatomia del Sistema nervoso. IV. Sulla fina anatomia delle circonvoluzioni cerebellari. Rivista Sperimentale di Freniatria e Medicina Legale delle Alienazioni Mentali 1883;9:1-17.
Retzius G. [Kleinere Mitteeilungen von dem Gebiete der Nervenhistologie].In: [I. Ueber die Golgi’schen Zellen und die Kletterfarsen Ramón y Cajal’s in der Kleinhirnrinde. Biologische Untersuchungen].[Book in German]. Stockholm, Neue Folge, Samson & Wallin; 1892. p 57-9.
Kölliker A. [Handbuch der Gewebelehre des Menschen. Nervensystem des Menschen und der Tiere].[Book in German]. Leipzig, Wilhelm Engelmann; 1896.
Jakob A. [Das Kleinhirn]. In: von Möllendorff W, editor. [Handbuch der Mikroskopischen Anatomie des Menschen].[Book in German]. Cham, Springer; 1928. p 674-916.
DOI: https://doi.org/10.1007/978-3-642-66443-4_12
Ramón y Cajal S. [Histologie du systéme nerveux de l’homme et des vertébrés].[Book in French]. Paris, Maloine; 1911.
Landau E. [Beitrag zur Kenntnis der Körnerschicht des Kleinhirns].[Article in German]. Vorl Mitt Anat Anz 1927;62:391-8.
Landau E. [Über cytoarchitektonische Bauunterschiede in der Körnerschicht des Kleinhirns].[Article in German]. Z Anat 1928;87:551-7.
DOI: https://doi.org/10.1007/BF02134402
Landau E. [La cellule synarmotique].[Article in French]. Bull Histol Appl 1932;9:159-68.
Landau E. [La cellule synarmotique dans le cervelet humain].[Article in French]. Arch Anat 1933;17:273-85.
Kesiunaité D. [Quelques mots sur la structure de la couche granuleuse du cervelet].[Article in French]. Bull Histol Appl 1930;7:156-61.
Löwenberg H. The presence of the synarmotical cell in the cerebellum of birds. Bio Morph 1938;1:273-80.
Müller T. Large nerve cells with long axons in the granular layer and white matter of the murine cerebellum. J Anat 1994;184:419-23.
Flace P, Lorusso L, Laiso G, Rizzi A, Cagiano R, Nico B, et al. Calbindin-D28k immunoreactivity in the human cerebellar cortex. Anat Rec 2014;297:1306-15.
DOI: https://doi.org/10.1002/ar.22921
Chan-Palay V. Fine structure of labelled axons in the cerebellar cortex and nuclei of rodents and primates after intraventricular infusions with tritiated serotonin. Anat Embryol (Berl) 1975;148:235-65.
DOI: https://doi.org/10.1007/BF00319846
Hámori J, Mezey E. Serial and triadic synapses in the cerebellar nuclei of the cat. Exp Brain Res 1977;30:259-73.
DOI: https://doi.org/10.1007/BF00237255
Katsetos CD, Frankfurter A, Christakos S, Mancall EL, Vlachos IN, Urich H. Differential localization of class III, betatubulin isotype and calbindin-D28k defines distinct neuronal types in the developing human cerebellar cortex. J Neuropathol Exp Neurol 1993;52:655-66.
DOI: https://doi.org/10.1097/00005072-199311000-00013
Lainé J, Axelrad H. Extending the cerebellar Lugaro cell class. Neuroscience 2002;115:363-74.
DOI: https://doi.org/10.1016/S0306-4522(02)00421-9
Flace P, Cacciola A, Milardi D, Basile GA, Anastasi G. Immunohistochemical and tractographic approaches on the human cerebellar dopaminergic system. Proc. 28th Nat. Congr. Italian Group for the Study of Neuromorphology (GISN), Florence, 2018; p. 14.
Attaai AH, Noreldin AE, Abdel-maksoud FM, Hussein MT. An updated investigation on the dromedary camel cerebellum (Camelus dromedarius) with special insight into the distribution of calcium-binding proteins. Sci Rep 2020;10:21157.
DOI: https://doi.org/10.1038/s41598-020-78192-7
Flace P, Lorusso L, Benagiano V, Ambrosi G. Double labelling immunocytochemical tecniques reveal colocalizations of GAD with motilin or VIP in the human cerebellar cortex. Proc. 15th Na.t Congr. Italian Group for the Study of Neuromorphology (GISN), Bologna, 2005; p. 18. Acad Sci Bologna Inst 2006.
Benagiano V, Flace P, Lorusso L, Rizzi A, Bosco L, Cagiano R, Ambrosi G. Vasoactive intestinal polypeptide immunoreactivity in the human cerebellum: qualitative and quantitative analyses. J Anat 2009;215:256-66.
DOI: https://doi.org/10.1111/j.1469-7580.2009.01110.x
Flace P, Livrea P, Galletta D, Gulisano M, Gennarini G. Translational study of the human cerebellar dopaminergic system, its interconnections and role in neurologic and psychiatric disorders. Proc. 30th Nat. Conf. Italian Group for the Study of Neuromorphology (GISN), Torinno, 2020; p. 15. Eur J Histochem 2020;64:3200.
DOI: https://doi.org/10.21203/rs.3.rs-30289/v1
Flace P, Livrea P, Basile G, Galletta D, Bizzoca A, Gennarini G, et al. The cerebellar dopaminergic system. Front Syst Neurosci 2021;15:650614.
DOI: https://doi.org/10.3389/fnsys.2021.650614
Bizzoca A, Virgintino D, Lorusso L, Buttiglione M, Yoshida L, Polizzi A, et al. Transgenic mice expressing F3/contactin from the TAG-1 promoter exhibit developmentally regulated changes in the differentiation of cerebellar neurons. Development 2003;130:29-43.
DOI: https://doi.org/10.1242/dev.00183
Bizzoca A, Corsi P, Gennarini G. The mouse F3/contactin glycoprotein: structural features, functional properties and developmental significance of its regulated expression. Cell Adh Migr 2009;3:53-63.
DOI: https://doi.org/10.4161/cam.3.1.7462
Bizzoca A, Jirillo E, Flace P, Gennarini G. Overall role of contactins expression in neurodevelopmental events and contribution to neurological disorders. CNS Neurol Disord Drug Targets 2022;22:1176-93.
DOI: https://doi.org/10.2174/1871527322666221212160048
Honnorat J, Saiz A, Giometto B, Vincent A, Brieva L, de Andres C, et al. Cerebellar ataxia with anti-glutamic acid decarboxylase antibodies: study of 14 patients. Arch Neurol 2001;58:225-30.
DOI: https://doi.org/10.1001/archneur.58.2.225
Manto M, Honnorat J, Hampe CS, Guerra-Narbona R, López-Ramos JC, Delgado-Garcia JM, et al. Disease-specific monoclonal antibodies targeting glutamate decarboxylase impair GABAergic neurotransmission and affect motor learning and behavioral functions. Front Behav Neurosci 2015;9:78.
DOI: https://doi.org/10.3389/fnbeh.2015.00078
Manto M. Mitoma H, Hampe CS. Anti-GAD Antibodies and the cerebellum: where do we stand? Cerebellum 2019;18:153-6.
DOI: https://doi.org/10.1007/s12311-018-0986-6
Mitoma H, Hadjivassiliou M, Honnorat J. Guidelines for treatment of immune-mediated cerebellar ataxias. Cerebellum Ataxias 2015;2:14.
DOI: https://doi.org/10.1186/s40673-015-0034-y
Mitoma H, Adhikari K, Aeschlimann D, Chattopadhyay P, Hadjivassiliou, M, Hampe CS. et al. Consensus paper: neuroimmune mechanisms of cerebellar ataxias. Cerebellum 2016;15:213-32.
DOI: https://doi.org/10.1007/s12311-015-0664-x
Mitoma H, Manto M, Hampe CS. Pathogenic roles of glutamic acid decarboxylase 65 autoantibodies in cerebellar ataxias. J Immunol Res 2017;2017:2913297.
DOI: https://doi.org/10.1155/2017/2913297
Mitoma H, Song SY, Ishida K, Yamakuni T, Kobayashi T, Mizusawa, H. Presynaptic impairment of cerebellar inhibitory synapses by an autoantibody to glutamate decarboxylase. J Neurol Sci 2000;175:40-4.
DOI: https://doi.org/10.1016/S0022-510X(00)00272-0
Mitoma H, Ishida K, Shizuka-Ikeda M, Mizusawa, H. Dual impairment of GABAA- and GABAB-receptor-mediated synaptic responses by autoantibodies to glutamic acid decarboxylase. J Neurol Sci 2003;208:51-6.
DOI: https://doi.org/10.1016/S0022-510X(02)00423-9
Kono S, Miyajima H, Sugimoto M, Suzuki Y, Takahashi Y, Hishida A. Stiff-person syndrome associated with cerebellar ataxia and high glutamic acid decarboxylase antibody titer. Intern Med 2001;40:968-71.
DOI: https://doi.org/10.2169/internalmedicine.40.968
Ishida K, Mitoma H, Wada Y, Oka T, Shibahara J, Saito Y, et al. Selective loss of Purkinje cells in a patient with anti-glutamic acid decarboxylase antibody-associated cerebellar ataxia. J Neurol Neurosurg Psychiatry 2007;78:190-2.
DOI: https://doi.org/10.1136/jnnp.2006.091116
Ishida K, Mitoma H, Mizusawa H. Reversibility of cerebellar GABAergic synapse impairment induced by anti-glutamic acid decarboxylase autoantibodies. J Neurol Sci 2008;271:186-90.
DOI: https://doi.org/10.1016/j.jns.2008.04.019
Joubert B, Rostásy K, Honnorat J. Immune-mediated ataxias. Handb Clin Neurol 2018;155:313-32.
DOI: https://doi.org/10.1016/B978-0-444-64189-2.00021-4
Tohid H. Anti-glutamic acid decarboxylase antibody positive neurological syndromes. Neurosciences (Riyadh) 2016;21:215-22.
DOI: https://doi.org/10.17712/nsj.2016.3.20150596
How to Cite
Flace, P., Galletta, D., Bizzoca, A., Gennarini, G., & Livrea, P. (2024). A candidate projective neuron type of the cerebellar cortex: the synarmotic neuron. European Journal of Histochemistry, 68(2). https://doi.org/10.4081/ejh.2024.3954
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