Abstract
The cerebellar cholinergic system belongs to the third type of afferent nerve fiber system (after the climbing and mossy fibers), and has important modulatory effects on cerebellar circuits and cerebellar-mediated functions. In this report, we review the cerebellar cholinergic system, including cholinergic origins and innervations, acetylcholine receptor expression and distributions, cholinergic modulations of neuronal firing and synaptic plasticity, the cholinergic role in cerebellar-mediated integral functions, and cholinergic changes during development and aging. Because some motor and mental disorders, such as cerebellar ataxia and autism, are accompanied with cerebellar cholinergic disorders, we also discuss the correlations between cerebellar cholinergic dysfunctions and these disorders. The cerebellar cholinergic input plays an important role in the modulation of cerebellar functions; therefore, cholinergic abnormalities could induce physiological dysfunctions.
Funding source: Natural Science Foundation of Anhui Province
Award Identifier / Grant number: 1308085MH127
Funding statement: This research was supported by grants from the Natural Science Foundation of Anhui Province (no. 1308085MH127) and the Postdoctoral Foundation of Jiangsu Province.
Acknowledgments
This research was supported by grants from the Natural Science Foundation of Anhui Province (no. 1308085MH127) and the Postdoctoral Foundation of Jiangsu Province.
Conflict of interest statement: The authors declare no conflict of interests.
References
Andre, P., Pompeiano, O., and White, S.R. (1993). Activation of muscarinic receptors induces a long-lasting enhancement of Purkinje cell responses to glutamate. Brain Res. 617, 28–36.10.1016/0006-8993(93)90608-PSearch in Google Scholar
Andre, P., Fascetti, F., Pompeiano, O., and White, S.R. (1994). The muscarinic agonist, bethanechol, enhances GABA-induced inhibition of Purkinje cells in the cerebellar cortex. Brain Res. 637, 1–9.10.1016/0006-8993(94)91210-6Search in Google Scholar
Anju, T.R., Ajayan, M.S., and Paulose, C.S. (2013). Disruption of cerebellar cholinergic system in hypoxic neonatal rats and its regulation with glucose, oxygen and epinephrine resuscitations. Neuroscience 236, 253–261.10.1016/j.neuroscience.2012.12.056Search in Google Scholar PubMed
Antony, S., Kumar, P., Mathew, J., Anju, T., and Paulose, C. (2010). Hypoglycemia induced changes in cholinergic receptor expression in the cerebellum of diabetic rats. J. Biomed. Sci. 17, 7.10.1186/1423-0127-17-7Search in Google Scholar PubMed PubMed Central
Araujo, D., Lapchak, P., Meaney, M., Collier, B., and Quirion, R. (1990). Effects of aging on nicotinic and muscarinic autoreceptor function in the rat brain: relationship to presynaptic cholinergic markers and binding sites. J. Neurosci. 10, 3069–3078.10.1523/JNEUROSCI.10-09-03069.1990Search in Google Scholar
Asin, K., Satoh, K., and Fibiger, H. (1984). Regional cerebellar choline acetyltransferase activity following peduncular lesions. Exp. Brain Res. 53, 370–373.10.1007/BF00238167Search in Google Scholar PubMed
Barmack, N., Baughman, R., and Eckenstein, F. (1992a). Cholinergic innervation of the cerebellum of the rat by secondary vestibular afferents. Ann. NY Acad. Sci. 656, 566–579.10.1111/j.1749-6632.1992.tb25236.xSearch in Google Scholar PubMed
Barmack, N., Baughman, R., Eckenstein, F., and Shojaku, H. (1992b). Secondary vestibular cholinergic projection to the cerebellum of rabbit and rat as revealed by choline acetyltransferase immunohistochemistry, retrograde and orthograde tracers. J. Comp. Neurol. 317, 250–270.10.1002/cne.903170304Search in Google Scholar PubMed
Basu, N., Stamler, C.J., Loua, K.M., and Chan, H.M. (2005). An interspecies comparison of mercury inhibition on muscarinic acetylcholine receptor binding in the cerebral cortex and cerebellum. Toxicol. Appl. Pharmacol. 205, 71–76.10.1016/j.taap.2004.09.009Search in Google Scholar PubMed
Chauhan, P.S., Misra, U.K., Kalita, J., Chandravanshi, L.P., and Khanna, V.K. (2016). Memory and learning seems to be related to cholinergic dysfunction in the JE rat model. Physiol. Behav. 156, 148–155.10.1016/j.physbeh.2016.01.006Search in Google Scholar PubMed
Clos, J., Ghandour, S., Eberhart, R., Vincendon, G., and Gombos, G. (1989). The cholinergic system in developing cerebellum: comparative study of normal, hypothyroid and underfed rats. Dev. Neurosci. 11, 188–204.10.1159/000111898Search in Google Scholar
Court, J.A., Perry, E.K., Spurden, D., Griffiths, M., Kerwin, J.M., Morris, C.M., Johnson, M., Oakley, A.E., Birdsall, N.J., Clementi, F., et al. (1995). The role of the cholinergic system in the development of the human cerebellum. Brain Res. Dev. Brain Res. 90, 159–167.10.1016/0165-3806(96)83496-1Search in Google Scholar
Crawford, J.M., Curtis, D.R., Voorhoeve, P.E., and Wilson, V.J. (1966). Acetylcholine sensitivity of cerebellar neurones in the cat. J. Physiol. 186, 139–165.10.1113/jphysiol.1966.sp008025Search in Google Scholar
Dar, M.S., Bowman, E.R., and Li, C. (1994). Intracerebellar nicotinic-cholinergic participation in the cerebellar adenosinergic modulation of ethanol-induced motor incoordination in mice. Brain Res. 644, 117–127.10.1016/0006-8993(94)90354-9Search in Google Scholar
De Filippi, G., Baldwinson, T., and Sher, E. (2001). Evidence for nicotinic acetylcholine receptor activation in rat cerebellar slices. Pharmacol. Biochem. Behav. 70, 447–455.10.1016/S0091-3057(01)00653-0Search in Google Scholar
de Lacalle, S., Hersh, L.B., and Saper, C.B. (1993). Cholinergic innervation of the human cerebellum. J. Comp. Neurol. 328, 364–376.10.1002/cne.903280304Search in Google Scholar
de Toro, E.D., Juíz, J.M., Smillie, F.I., Lindstrom, J., and Criado, M. (1997). Expression of α7 neuronal nicotinic receptors during postnatal development of the rat cerebellum. Brain Res. Dev. Brain Res. 98, 125–133.10.1016/S0165-3806(96)00185-XSearch in Google Scholar
Ferrari, F., Gorini, A., and Villa, R.F. (2015). Energy metabolism of synaptosomes from different neuronal systems of rat cerebellum during aging: a functional proteomic characterization. Neurochem. Res. 40, 172–185.10.1007/s11064-014-1482-0Search in Google Scholar PubMed
Fucile, S., Renzi, M., Lauro, C., Limatola, C., Ciotti, T., and Eusebi, F. (2004). Nicotinic cholinergic stimulation promotes survival and reduces motility of cultured rat cerebellar granule cells. Neuroscience 127, 53–61.10.1016/j.neuroscience.2004.04.017Search in Google Scholar PubMed
Gilman, S., Koeppe, R.A., Nan, B., Wang, C.N., Wang, X., Junck, L., Chervin, R.D., Consens, F., and Bhaumik, A. (2010). Cerebral cortical and subcortical cholinergic deficits in parkinsonian syndromes. Neurology 74, 1416–1423.10.1212/WNL.0b013e3181dc1a55Search in Google Scholar PubMed PubMed Central
Graham, A., Court, J., Martin-Ruiz, C., Jaros, E., Perry, R., Volsen, S., Bose, S., Evans, N., Ince, P., and Kuryatov, A. (2002). Immunohistochemical localisation of nicotinic acetylcholine receptor subunits in human cerebellum. Neuroscience 113, 493–507.10.1016/S0306-4522(02)00223-3Search in Google Scholar
Haga, T. (2013). Molecular properties of muscarinic acetylcholine receptors. Proc. Jpn. Acad. Ser. B. Phys. Biol. Sci. 89, 226–256.10.2183/pjab.89.226Search in Google Scholar
Hirano, S., Shinotoh, H., Arai, K., Aotsuka, A., Yasuno, F., Tanaka, N., Ota, T., Sato, K., Fukushi, K., and Tanada, S. (2008). PET study of brain acetylcholinesterase in cerebellar degenerative disorders. Mov. Disord. 23, 1154–1160.10.1002/mds.22056Search in Google Scholar
Huang, L., Abbott, L., and Winzer-Serhan, U. (2007). Effects of chronic neonatal nicotine exposure on nicotinic acetylcholine receptor binding, cell death and morphology in hippocampus and cerebellum. Neuroscience 146, 1854–1868.10.1016/j.neuroscience.2007.03.008Search in Google Scholar
Illing, R.B. (1990). A subtype of cerebellar Golgi cells may be cholinergic. Brain Res. 522, 267–274.10.1016/0006-8993(90)91471-RSearch in Google Scholar
Ito, M. (2012). The Cerebellum: Brain for an Implicit Self (Upper Saddle River, NJ: FT Press).Search in Google Scholar
Jaarsma, D., Levey, A.I., Frostholm, A., Rotter, A., and Voogd, J. (1995). Light-microscopic distribution and parasagittal organisation of muscarinic receptors in rabbit cerebellar cortex. J. Chem. Neuroanat. 9, 241–259.10.1016/0891-0618(95)00089-5Search in Google Scholar
Jaarsma, D., Dino, M., Cozzari, C., and Mugnaini, E. (1996). Cerebellar choline acetyltransferase positive mossy fibres and their granule and unipolar brush cell targets: a model for central cholinergic nicotinic neurotransmission. J. Neurocytol. 25, 829–842.10.1007/BF02284845Search in Google Scholar
Jaarsma, D., Ruigrok, T.J., Caffe, R., Cozzari, C., Levey, A.I., Mugnaini, E., and Voogd, J. (1997). Cholinergic innervation and receptors in the cerebellum. Prog. Brain Res. 114, 67–96.10.1016/S0079-6123(08)63359-2Search in Google Scholar
Kan, K.S., Chao, L.P., and Eng, L.F. (1978). Immunohistochemical localization of choline acetyltransferase in rabbit spinal cord and cerebellum. Brain Res. 146, 221–229.10.1016/0006-8993(78)90970-8Search in Google Scholar
Kandel, E.R. (2013). Principles of Neural Science (New York: McGraw-Hill Medical Press), pp. 1038–1055.Search in Google Scholar
Karczmar, A.G. (2007). Exploring the Vertebrate Central Cholinergic Nervous System (Berkeley, CA: Apress), pp. 33–79.10.1007/978-0-387-46526-5_2Search in Google Scholar
Kawa, K. (2002). Acute synaptic modulation by nicotinic agonists in developing cerebellar Purkinje cells of the rat. J. Physiol. 538, 87–102.10.1113/jphysiol.2001.012885Search in Google Scholar
Kruse, A.C., Kobilka, B.K., Gautam, D., Sexton, P.M., Christopoulos, A., and Wess, J. (2014). Muscarinic acetylcholine receptors: novel opportunities for drug development. Nat. Rev. Drug. Discov. 13, 549–560.10.1038/nrd4295Search in Google Scholar
Lan, C.T., Wen, C.Y., Tan, C.K., Ling, E.A., and Shieh, J.Y. (1995). Multiple origins of cerebellar cholinergic afferents from the lower brainstem in the gerbil. J. Anat. 186, 549–561.Search in Google Scholar
Lee, M., Martin-Ruiz, C., Graham, A., Court, J., Jaros, E., Perry, R., Iversen, P., Bauman, M., and Perry, E. (2002). Nicotinic receptor abnormalities in the cerebellar cortex in autism. Brain 125, 1483–1495.10.1093/brain/awf160Search in Google Scholar
Manyam, B.V., Giacobini, E., Ferraro, T.N., and Hare, T.A. (1990). Cerebrospinal fluid as a reflector of central cholinergic and amino acid neurotransmitter activity in cerebellar ataxia. Arch. Neurol. 47, 1194–1199.10.1001/archneur.1990.00530110048016Search in Google Scholar
Martin-Ruiz, C.M., Lee, M., Perry, R.H., Baumann, M., Court, J.A., and Perry, E.K. (2004). Molecular analysis of nicotinic receptor expression in autism. Brain Res. Mol. Brain Res. 123, 81–90.10.1016/j.molbrainres.2004.01.003Search in Google Scholar
McCance, I. and Phillis, J.V.V. (1968). Cholinergic mechanisms in the cerebellar cortex. Int. J. Neuropharmacol. 7, 447–462.10.1016/0028-3908(68)90044-0Search in Google Scholar
Morin, A.M. and Wasterlain, C.G. (1980). Aging and rat brain muscarinic receptors as measured by quinuclidinyl benzilate binding. Neurochem. Res. 5, 301–308.10.1007/BF00964618Search in Google Scholar PubMed
Neustadt, A., Frostholm, A., and Rotter, A. (1988). Topographical distribution of muscarinic cholinergic receptors in the cerebellar cortex of the mouse, rat, guinea pig, and rabbit: a species comparison. J. Comp. Neurol. 272, 317–330.10.1002/cne.902720303Search in Google Scholar PubMed
Nisimaru, N. (2004). Cardiovascular modules in the cerebellum. Jpn. J. Physiol. 54, 431–448.10.2170/jjphysiol.54.431Search in Google Scholar PubMed
O’Leary, K. and Leslie, F. (2003). Developmental regulation of nicotinic acetylcholine receptor-mediated [3H] norepinephrine release from rat cerebellum. J. Neurochem. 84, 952–959.10.1046/j.1471-4159.2003.01575.xSearch in Google Scholar PubMed
Ojima, H., Kawajiri, S., and Yamasaki, T. (1989). Cholinergic innervation of the rat cerebellum: qualitative and quantitative analyses of elements immunoreactive to a monoclonal antibody against choline acetyltransferase. J. Comp. Neurol. 290, 41–52.10.1002/cne.902900104Search in Google Scholar
Opanashuk, L.A., Pauly, J.R., and Hauser, K.F. (2001). Effect of nicotine on cerebellar granule neuron development. Eur. J. Neurosci. 13, 48–56.10.1046/j.1460-9568.2001.01359.xSearch in Google Scholar
Picciotto, M.R., Higley, M.J., and Mineur, Y.S. (2012). Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior. Neuron 76, 116–129.10.1016/j.neuron.2012.08.036Search in Google Scholar
Prestori, F., Bonardi, C., Mapelli, L., Lombardo, P., Goselink, R., De Stefano, M.E., Gandolfi, D., Mapelli, J., Bertrand, D., Schonewille, M., et al. (2013). Gating of long-term potentiation by nicotinic acetylcholine receptors at the cerebellum input stage. PLoS One 8, e64828.10.1371/journal.pone.0064828Search in Google Scholar
Ramanathan, D.S., Conner, J.M., Anilkumar, A.A., and Tuszynski, M.H. (2014). Cholinergic systems are essential for late-stage maturation and refinement of motor cortical circuits. J. Neurophysiol. 113, 1585–1597.10.1152/jn.00408.2014Search in Google Scholar
Reddy, G.R., Basha, M.R., Devi, C.B., Suresh, A., Baker, J.L., Shafeek, A., Heinz, J., and Chetty, C.S. (2003). Lead induced effects on acetylcholinesterase activity in cerebellum and hippocampus of developing rat. Int. J. Dev. Neurosci. 21, 347–352.10.1016/S0736-5748(03)00071-6Search in Google Scholar
Rinaldo, L. and Hansel, C. (2013). Muscarinic acetylcholine receptor activation blocks long-term potentiation at cerebellar parallel fiber-Purkinje cell synapses via cannabinoid signaling. Proc. Natl. Acad. Sci. U. S. A. 110, 11181–11186.10.1073/pnas.1221803110Search in Google Scholar
Roda, E., Coccini, T., Acerbi, D., Castoldi, A., Bernocchi, G., and Manzo, L. (2008). Cerebellum cholinergic muscarinic receptor (subtype-2 and-3) and cytoarchitecture after developmental exposure to methylmercury: an immunohistochemical study in rat. J. Chem. Neuroanat. 35, 285–294.10.1016/j.jchemneu.2008.01.003Search in Google Scholar
Schweighofer, N., Doya, K., and Kuroda, S. (2004). Cerebellar aminergic neuromodulation: towards a functional understanding. Brain Res. Rev. 44, 103–116.10.1016/j.brainresrev.2003.10.004Search in Google Scholar
Takayasu, Y., Iino, M., Furuya, N., and Ozawa, S. (2003). Muscarine-induced increase in frequency of spontaneous EPSCs in Purkinje cells in the vestibulo-cerebellum of the rat. J. Neurosci. 23, 6200–6208.10.1523/JNEUROSCI.23-15-06200.2003Search in Google Scholar
Tayebati, S.K., Vitali, D., Scordella, S., and Amenta, F. (2001). Muscarinic cholinergic receptors subtypes in rat cerebellar cortex: light microscope autoradiography of age-related changes. Brain Res. 889, 256–259.10.1016/S0006-8993(00)03146-2Search in Google Scholar
Tizabi, Y., Al-Namaeh, M., Manaye, K.F., and Taylor, R.E. (2003). Protective effects of nicotine on ethanol-induced toxicity in cultured cerebellar granule cells. Neurotox. Res. 5, 315–321.10.1007/BF03033151Search in Google Scholar
Tizabi, Y., Manaye, K.F., and Taylor, R.E. (2005). Nicotine blocks ethanol-induced apoptosis in primary cultures of rat cerebral cortical and cerebellar granule cells. Neurotox. Res. 7, 319–322.10.1007/BF03033888Search in Google Scholar
Turner, J.R. and Kellar, K.J. (2005). Nicotinic cholinergic receptors in the rat cerebellum: multiple heteromeric subtypes. J. Neurosci. 25, 9258–9265.10.1523/JNEUROSCI.2112-05.2005Search in Google Scholar
Van der Steen, J. and Tan, H. (1997). Cholinergic control in the floccular cerebellum of the rabbit. Prog. Brain Res. 114, 335–345.10.1016/S0079-6123(08)63373-7Search in Google Scholar
Yan, G.M., Lin, S.Z., Irwin, R.P., and Paul, S.M. (1995). Activation of muscarinic cholinergic receptors blocks apoptosis of cultured cerebellar granule neurons. Mol. Pharmacol. 47, 248–257.10.1016/S0026-895X(25)08535-9Search in Google Scholar
Zhang, C.Z., Zhuang, Q.X., He, Y.C., Li, G.Y., Zhu, J.N., and Wang, J.J. (2014). 5-HT2A receptor-mediated excitation on cerebellar fastigial nucleus neurons and promotion of motor behaviors in rats. Pflüger’s Arch. 466, 1259–1271.10.1007/s00424-013-1378-xSearch in Google Scholar PubMed
Zhang, C., Sun, T., Zhou, P., Zhu, Q., and Zhang, L. (2016). Role of muscarinic acetylcholine receptor-2 in the cerebellar cortex in cardiovascular modulation in anaesthetized rats. Neurochem. Res. 41, 804–812.10.1007/s11064-015-1755-2Search in Google Scholar PubMed
Zhou, P., Zhu, Q., Liu, M., Li, J., Wang, Y., Zhang, C., and Hua, T. (2015). Muscarinic acetylcholine receptor in cerebellar cortex participates in acetylcholine-mediated blood depressor response in rats. Neurosci. Lett. 593, 129–133.10.1016/j.neulet.2015.03.036Search in Google Scholar PubMed
Zhu, Q., Zhou, P., Wang, S., Zhang, C., and Hua, T. (2015). A preliminary study on cerebellar acetylcholine-mediated blood pressure regulation in young and old rats. Exp. Gerontol. 63, 76–80.10.1016/j.exger.2015.02.003Search in Google Scholar PubMed
©2016 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Frontmatter
- The cholinergic system in the cerebellum: from structure to function
- Tanshinones and mental diseases: from chemistry to medicine
- Brain-derived neurotrophic factor: a mediator of inflammation-associated neurogenesis in Alzheimer’s disease
- SIRT1 as a therapeutic target for Alzheimer’s disease
- A systematic review of the neurobiological underpinnings of borderline personality disorder (BPD) in childhood and adolescence
- Neuroprotective properties of mitochondria-targeted antioxidants of the SkQ-type
- Imaging and machine learning techniques for diagnosis of Alzheimer’s disease
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Articles in the same Issue
- Frontmatter
- The cholinergic system in the cerebellum: from structure to function
- Tanshinones and mental diseases: from chemistry to medicine
- Brain-derived neurotrophic factor: a mediator of inflammation-associated neurogenesis in Alzheimer’s disease
- SIRT1 as a therapeutic target for Alzheimer’s disease
- A systematic review of the neurobiological underpinnings of borderline personality disorder (BPD) in childhood and adolescence
- Neuroprotective properties of mitochondria-targeted antioxidants of the SkQ-type
- Imaging and machine learning techniques for diagnosis of Alzheimer’s disease
- Resting state functional magnetic resonance imaging processing techniques in stroke studies