Serotonin and Synaptic Transmission in the Cerebellum

  • Moritoshi HironoEmail author
  • Fumihito Saitow
  • Hidenori Suzuki
Living reference work entry


The neurotransmitter serotonin (5-hydroxytryptamine [5-HT]) is widely distributed in the central nervous system (CNS) and is involved in various physiological functions. In the cerebellum, serotonergic fibers are the third largest population of afferent fibers, innervating and affecting the functions of various regions. Although there are a number of studies showing that 5-HT influences activity of cerebellar circuitry, the physiological functions of 5-HT in the cerebellum remain largely unknown. This chapter will focus on the modulatory actions of 5-HT on synaptic transmission in the cerebellar cortex and deep cerebellar nuclei (DCN), which are key areas that play a role in cerebellar information processing. First, the literature describing 5-HT-mediated modulatory effects on glutamatergic and GABAergic/glycinergic transmission within individual cerebellar regions are reviewed. This article proposes that (1) 5-HT widely modulates the information flow from Purkinje cells in the cerebellar cortex and (2) 5-HT facilitates spontaneous firing of DCN neurons directly, but it also suppresses synaptic transmission and the expression of long-term synaptic plasticity in DCN neurons. Finally, some developmental neurological disorders that may be attributed to malfunctions in the 5-HT system will be discussed.


Serotonin Modulation Transmitter release Serotonin receptor Synaptic transmission Cerebellar cortex Deep cerebellar nuclei Purkinje cell Granule cell Golgi cell Lugaro cell Globular cell Basket/stellate cell Developmental disorder Autism Attention-deficit/hyperactivity disorder Electrophysiology Inhibitory postsynaptic current Excitatory postsynaptic current Synaptic plasticity Long-term potentiation Long-term depression Mossy fiber Rebound depolarization 


  1. Aizenman CD, Linden DJ (1999) Regulation of the rebound depolarization and spontaneous firing patterns of deep nuclear neurons in slices of rat cerebellum. J Neurophysiol 82:1697–1709PubMedCrossRefGoogle Scholar
  2. Aizenman CD, Manis PB, Linden DJ (1998) Polarity of long-term synaptic gain change is related to postsynaptic spike firing at a cerebellar inhibitory synapse. Neuron 21:827–835PubMedCrossRefGoogle Scholar
  3. Alvarez MI, Lacruz C, Toledano-Diaz A et al (2008) Calretinin-immunopositive cells and fibers in the cerebellar cortex of normal sheep. Cerebellum 7:417–429PubMedCrossRefGoogle Scholar
  4. Armstrong DL, Hay M, Terrian DM (1987) Modulation of cerebellar granule cell activity by iontophoretic application of serotonergic agents. Brain Res Bull 19:699–704PubMedCrossRefGoogle Scholar
  5. Bishop GA, Ho RH (1985) The distribution and origin of serotonin immunoreactivity in the rat cerebellum. Brain Res 331:195–207PubMedCrossRefGoogle Scholar
  6. Bobillier P, Seguin S, Petitjean F et al (1976) The raphe nuclei of the cat brain stem: a topographical atlas of their efferent projections as revealed by autoradiography. Brain Res 113:449–486PubMedCrossRefGoogle Scholar
  7. Bockaert J, Claeysen S, Becamel C et al (2006) Neuronal 5-HT metabotropic receptors: fine-tuning of their structure, signaling, and roles in synaptic modulation. Cell Tissue Res 326:553–572PubMedCrossRefGoogle Scholar
  8. Chess AC, Green JT (2008) Abnormal topography and altered acquisition of conditioned eyeblink responses in a rodent model of attention-deficit/hyperactivity disorder. Behav Neurosci 122:63–74PubMedCrossRefGoogle Scholar
  9. Chugani DC, Muzuki O, Behen M et al (1999) Developmental changes in brain serotonin synthesis capacity in autistic and nonautistic children. Ann Neurol 45:287–295PubMedCrossRefGoogle Scholar
  10. Ciesielski KT, Harris RJ, Hart BL et al (1997) Cerebellar hypoplasia and frontal lobe cognitive deficits in disorders of early childhood. Neuropsychologia 35:643–655PubMedCrossRefGoogle Scholar
  11. Ciranna L (2006) Serotonin as a modulator of glutamate- and GABA-mediated neurotransmission: implications in physiological functions and in pathology. Curr Neuropharmacol 4:101–114PubMedPubMedCentralCrossRefGoogle Scholar
  12. Courchesne E (1997) Brainstem, cerebellar and limbic neuroanatomical abnormalities in autism. Curr Opin Neurobiol 7:269–278PubMedCrossRefGoogle Scholar
  13. Crook JD, Hendrickson A, Erickson A et al (2007) Purkinje cell axon collaterals terminate on Cat-301+ neurons in Macaca monkey cerebellum. Neuroscience 149:834–844PubMedPubMedCentralCrossRefGoogle Scholar
  14. Darrow EJ, Strahlendorf HK, Strahlendorf JC (1990) Response of cerebellar Purkinje cells to serotonin and the 5-HT1A agonists 8-OH-DPAT and ipsapirone in vitro. Eur J Pharmacol 175:145–153PubMedCrossRefGoogle Scholar
  15. Dean I, Robertson SJ, Edwards FA (2003) Serotonin drives a novel GABAergic synaptic current recorded in rat cerebellar Purkinje cells: a Lugaro cell to Purkinje cell synapse. J Neurosci 23:4457–4469PubMedCrossRefGoogle Scholar
  16. Di Mauro M, Fretto G, Caldera M et al (2003) Noradrenaline and 5-hydroxytryptamine in cerebellar nuclei of the rat: functional effects on neuronal firing. Neurosci Lett 347:101–105PubMedCrossRefGoogle Scholar
  17. Dieudonné S (2001) Serotonergic neuromodulation in the cerebellar cortex: cellular, synaptic, and molecular basis. Neuroscientist 7:207–219PubMedCrossRefGoogle Scholar
  18. Dieudonné S, Dumoulin A (2000) Serotonin-driven long-range inhibitory connections in the cerebellar cortex. J Neurosci 20:1837–1848PubMedCrossRefGoogle Scholar
  19. Dumoulin A, Triller A, Dieudonné S (2001) IPSC kinetics at identified GABAergic and mixed GABAergic and glycinergic synapses onto cerebellar Golgi cells. J Neurosci 21:6045–6057PubMedCrossRefGoogle Scholar
  20. Frings M, Gaertner K, Buderath P et al (2010) Timing of conditioned eyeblink responses is impaired in children with attention-deficit/hyperactivity disorder. Exp Brain Res 201:167–176PubMedCrossRefGoogle Scholar
  21. Gardette R, Krupa M, Crepel F (1987) Differential effects of serotonin on the spontaneous discharge and on the excitatory amino acid-induced responses of deep cerebellar nuclei neurons in rat cerebellar slices. Neuroscience 23:491–500PubMedCrossRefGoogle Scholar
  22. Gauck V, Jaeger D (2000) The control of rate and timing of spikes in the deep cerebellar nuclei by inhibition. J Neurosci 20:3006–3016PubMedCrossRefGoogle Scholar
  23. Geurts FJ, De Schutter E, Timmermans JP (2002) Localization of 5-HT2A, 5-HT3, 5-HT5A and 5-HT7 receptor-like immunoreactivity in the rat cerebellum. J Chem Neuroanat 24:65–74PubMedCrossRefGoogle Scholar
  24. Gonzalez-Burgos I, Feria-Velasco A (2008) Serotonin/dopamine interaction in memory formation. Prog Brain Res 172:603–623PubMedCrossRefGoogle Scholar
  25. Gu F, Chauhan V, Chauhan A (2017) Monoamine oxidase-A and B activities in the cerebellum and frontal cortex of children and young adults with autism. J Neurosci Res 95:1965–1972PubMedCrossRefGoogle Scholar
  26. Hirono M, Saitow F, Kudo M et al (2012) Cerebellar globular cells receive monoaminergic excitation and monosynaptic inhibition from Purkinje cells. PLoS One 7:e29663PubMedPubMedCentralCrossRefGoogle Scholar
  27. Hirono M, Nagao S, Yanagawa Y et al (2017) Monoaminergic modulation of GABAergic transmission onto cerebellar globular cells. Neuropharmacology 118:79–89PubMedCrossRefGoogle Scholar
  28. Jaarsma D, Ruigrok TJ, Caffe R et al (1997) Cholinergic innervation and receptors in the cerebellum. Prog Brain Res 114:67–96PubMedCrossRefGoogle Scholar
  29. Kerr CW, Bishop GA (1991) Topographical organization in the origin of serotoninergic projections to different regions of the cat cerebellar cortex. J Comp Neurol 304:502–515PubMedCrossRefGoogle Scholar
  30. Kerr CW, Bishop GA (1992) The physiological effects of serotonin are mediated by the 5HT1Areceptor in the cat’s cerebellar cortex. Brain Res 591:253–260PubMedCrossRefGoogle Scholar
  31. Kitzman PH, Bishop GA (1994) The origin of serotoninergic afferents to the cat’s cerebellar nuclei. J Comp Neurol 340:541–550PubMedCrossRefGoogle Scholar
  32. Kitzman PH, Bishop GA (1997) The physiological effects of serotonin on spontaneous and amino acid-induced activation of cerebellar nuclear cells: an in vivo study in the cat. Prog Brain Res 114:209–223PubMedCrossRefGoogle Scholar
  33. Koekkoek SK, Hulscher HC, Dortland BR et al (2003) Cerebellar LTD and learning-dependent timing of conditioned eyelid responses. Science 301:1736–1739PubMedCrossRefGoogle Scholar
  34. Lainé J, Axelrad H (1996) Morphology of the Golgi-impregnated Lugaro cell in the rat cerebellar cortex: a reappraisal with a description of its axon. J Comp Neurol 375:618–640PubMedCrossRefGoogle Scholar
  35. Lainé J, Axelrad H (2002) Extending the cerebellar Lugaro cell class. Neuroscience 115:363–374PubMedCrossRefGoogle Scholar
  36. Lauder JM (1990) Ontogeny of the serotonergic system in the rat: serotonin as a developmental signal. Ann N Y Acad Sci 600:297–313PubMedCrossRefGoogle Scholar
  37. Lee M, Strahlendorf JC, Strahlendorf HK (1985) Modulatory action of serotonin on glutamate-induced excitation of cerebellar Purkinje cells. Brain Res 361:107–113PubMedCrossRefGoogle Scholar
  38. Li SJ, Wang Y, Strahlendorf HK et al (1993) Serotonin alters an inwardly rectifying current (Ih) in rat cerebellar Purkinje cells under voltage clamp. Brain Res 617:87–95PubMedCrossRefGoogle Scholar
  39. Lippiello P, Hoxha E, Speranza L et al (2016) The 5-HT7 receptor triggers cerebellar long-term synaptic depression via PKC-MAPK. Neuropharmacology 101:426–438PubMedCrossRefGoogle Scholar
  40. Lugaro E (1894) Sulle connessioni tra gli elemente nervosa della corteccia cerebellare con considerazioni generali sulsignificato fisiologico dei rapporti tra gli elementi nervosi. Riv Sper Freniatria 20:297–331Google Scholar
  41. Maura G, Raiteri M (1996) Serotonin 5-HT1D and 5-HT1Areceptors respectively mediate inhibition of glutamate release and inhibition of cyclic GMP production in rat cerebellum in vitro. J Neurochem 66:203–209PubMedCrossRefGoogle Scholar
  42. Maura G, Ricchetti A, Raiteri M (1986) Serotonin inhibits the depolarization-evoked release of endogenous glutamate from rat cerebellar nerve endings. Neurosci Lett 67:218–222PubMedCrossRefGoogle Scholar
  43. Maura G, Roccatagliata E, Ulivi M et al (1988) Serotonin-glutamate interaction in rat cerebellum: involvement of 5-HT1 and 5-HT2 receptors. Eur J Pharmacol 145:31–38PubMedCrossRefGoogle Scholar
  44. McCormick DA, Thompson RF (1984) Neuronal responses of the rabbit cerebellum during acquisition and performance of a classically conditioned nictitating membrane-eyelid response. J Neurosci 4:2811–2822PubMedCrossRefGoogle Scholar
  45. Millan MJ (2006) Multi-target strategies for the improved treatment of depressive states: conceptual foundations and neuronal substrates, drug discovery and therapeutic application. Pharmacol Therapeut 110:135–370CrossRefGoogle Scholar
  46. Millan MJ, Marin P, Bockaert J et al (2008) Signaling at G-protein-coupled serotonin receptors: recent advances and future research directions. Trends Pharmacol Sci 29:454–464PubMedCrossRefGoogle Scholar
  47. Mitoma H, Konishi S (1999) Monoaminergic long-term facilitation of GABA-mediated inhibitory transmission at cerebellar synapses. Neuroscience 88:871–883PubMedCrossRefGoogle Scholar
  48. Mitoma H, Kobayashi T, Song SY et al (1994) Enhancement by serotonin of GABA-mediated inhibitory synaptic currents in rat cerebellar Purkinje cells. Neurosci Lett 173:127–130PubMedCrossRefGoogle Scholar
  49. Molineux ML, McRory JE, McKay BE et al (2006) Specific T-type calcium channel isoforms are associated with distinct burst phenotypes in deep cerebellar nuclear neurons. Natl Acad Sci USA 103:5555–5560CrossRefGoogle Scholar
  50. Mouginot D, Gahwiler BH (1995) Characterization of synaptic connections between cortex and deep nuclei of the rat cerebellum in vitro. Neuroscience 64:699–712PubMedPubMedCentralCrossRefGoogle Scholar
  51. Muller CL, Anacker AMJ, Veenstra-VanderWeele J (2016) The serotonin system in autism spectrum disorder: from biomarker to animal models. Neuroscience 321:24–41PubMedCrossRefGoogle Scholar
  52. Murano M, Saitow F, Suzuki H (2011) Modulatory effects of serotonin on glutamatergic synaptic transmission and long-term depression in the deep cerebellar nuclei. Neuroscience 172:118–128PubMedCrossRefGoogle Scholar
  53. Nakai N, Nagano M, Saitow F et al (2017) Serotonin rebalances cortical tuning and behavior linked to autism symptoms in 15q11-13 CNV mice. Sci Adv 3:e1603001PubMedPubMedCentralCrossRefGoogle Scholar
  54. Oades RD (2008) Dopamine-serotonin interactions in attention-deficit hyperactivity disorder (ADHD). Prog Brain Res 172:543–565PubMedCrossRefGoogle Scholar
  55. Oades RD (2010) The role of serotonin in attention-deficit hyperactivity disorder (ADHD). Handb Behav Neurosci 21:565–584CrossRefGoogle Scholar
  56. Oostland M, Sellmeijer J, van Hooft JA (2011) Transient expression of functional serotonin 5-HT3 receptors by glutamatergic granule cells in the early postnatal mouse cerebellum. J Physiol 589:4837–4846PubMedPubMedCentralCrossRefGoogle Scholar
  57. Oostland M, Buijink MR, Teunisse GM et al (2014) Distinct temporal expression of 5-HT1A and 5-HT2A receptors on cerebellar granule cells in mic. Cerebellum 13:491–500PubMedPubMedCentralCrossRefGoogle Scholar
  58. Palay SL, Chan-Palay V (1974) Cerebellar cortex: cytology and organization. In: Cerebellar cortex: cytology and organization. Springer, BerlinCrossRefGoogle Scholar
  59. Peroutka SJ, Snyder SH (1979) Multiple serotonin receptors: differential binding of [3H]5-hydroxytryptamine, [3H]lysergic acid diethylamide and [3H]spiroperidol. Mol Pharmacol 16:687–699PubMedGoogle Scholar
  60. Pugh JR, Raman IM (2006) Potentiation of mossy fiber EPSCs in the cerebellar nuclei by NMDA receptor activation followed by postinhibitory rebound current. Neuron 51:113–123PubMedCrossRefGoogle Scholar
  61. Pugh JR, Raman IM (2008) Mechanisms of potentiation of mossy fiber EPSCs in the cerebellar nuclei by coincident synaptic excitation and inhibition. J Neurosci 28:10549–10560PubMedPubMedCentralCrossRefGoogle Scholar
  62. Rossi DJ, Hamann M (1998) Spillover-mediated transmission at inhibitory synapses promoted by high affinity alpha6 subunit GABA(A) receptors and glomerular geometry. Neuron 20:783–795PubMedCrossRefGoogle Scholar
  63. Saitoh O, Courchesne E, Egaas B et al (1995) Cross-sectional area of the posterior hippocampus in autistic patients with cerebellar and corpus callosum abnormalities. Neurology 45:317–324PubMedCrossRefGoogle Scholar
  64. Saitow F, Murano M, Suzuki H (2009) Modulatory effects of serotonin on GABAergic synaptic transmission and membrane properties in the deep cerebellar nuclei. J Neurophysiol 101:1361–1374PubMedCrossRefGoogle Scholar
  65. Schilling K, Oberdick J, Rossi F et al (2008) Besides Purkinje cells and granule neurons: an appraisal of the cell biology of the interneurons of the cerebellar cortex. Histochem Cell Biol 130:601–615PubMedCrossRefGoogle Scholar
  66. Shin SL, De Schutter E (2006) Dynamic synchronization of Purkinje cell simple spikes. J Neurophysiol 96:3485–3491PubMedCrossRefGoogle Scholar
  67. Shin SL, Hoebeek FE, Schonewille M et al (2007a) Regular patterns in cerebellar Purkinje cell simple spike trains. PLoS One 2:e485PubMedPubMedCentralCrossRefGoogle Scholar
  68. Shin SL, Rotter S, Aertsen A et al (2007b) Stochastic description of complex and simple spike firing in cerebellar Purkinje cells. Eur J Neurosci 25:785–794PubMedCrossRefGoogle Scholar
  69. Simat M, Parpan F, Fritschy JM (2007) Heterogeneity of glycinergic and gabaergic interneurons in the granule cell layer of mouse cerebellum. J Comp Neurol 500:71–83PubMedCrossRefGoogle Scholar
  70. Singer JH, Bellingham MC, Berger AJ (1996) Presynaptic inhibition of glutamatergic synaptic transmission to rat motoneurons by serotonin. J Neurophysiol 76:799–807PubMedCrossRefGoogle Scholar
  71. Skefos J, Cummings C, Enzer K et al (2014) Regional alterations in Purkinje cell density in patients with autism. PLoS One 9:e81255PubMedPubMedCentralCrossRefGoogle Scholar
  72. Sodhi MS, Sanders-Bush E (2004) Serotonin and brain development. Int Rev Neurobiol 59:111–174PubMedCrossRefGoogle Scholar
  73. Steinmetz JE, Logan CG, Rosen DJ et al (1987) Initial localization of the acoustic conditioned stimulus projection system to the cerebellum essential for classical eyelid conditioning. Proc Natl Acad Sci U S A 84:3531–3535PubMedPubMedCentralCrossRefGoogle Scholar
  74. Strahlendorf JC, Hubbard GD (1983) Serotonergic interactions with rat cerebellar Purkinje cells. Brain Res Bull 11:265–269PubMedCrossRefGoogle Scholar
  75. Strahlendorf JC, Lee M, Strahlendorf HK (1984) Effects of serotonin on cerebellar Purkinje cells are dependent on the baseline firing rate. Exp Brain Res 56:50–58PubMedCrossRefGoogle Scholar
  76. Suzuki R, Rygh LJ, Dickenson AH (2004) Bad news from the brain: descending 5-HT pathways that control spinal pain processing. Trends Pharmacol Sci 25:613–617PubMedCrossRefGoogle Scholar
  77. Takeuchi Y, Kimura H, Sano Y (1982) Immunohistochemical demonstration of the distribution of serotonin neurons in the brainstem of the rat and cat. Cell Tissue Res 224:247–267PubMedCrossRefGoogle Scholar
  78. Tamada K, Tomonaga S, Hatanaka F et al (2010) Decreased exploratory activity in a mouse model of 15q duplication syndrome; implications for disturbance of serotonin signaling. PLoS One 5:e15126PubMedPubMedCentralCrossRefGoogle Scholar
  79. Tecott LH (2007) Serotonin and the orchestration of energy balance. Cell Metab 6:352–361PubMedCrossRefGoogle Scholar
  80. Teune TM, Van der Burg J, de Zeeuw CI et al (1998) Single Purkinje cell can innervate multiple classes of projection neurons in the cerebellar nuclei of the rat: a light microscopic and ultrastructural triple-tracer study in the rat. J Comp Neurol 392:164–178PubMedPubMedCentralCrossRefGoogle Scholar
  81. Thellung S, Barzizza A, Maura G et al (1993) Serotonergic inhibition of the mossy fibre–granule cell glutamate transmission in rat cerebellar slices. Naunyn Schmiedeberg’s Arch Pharmacol 348:347–351CrossRefGoogle Scholar
  82. Ursin R (2002) Serotonin and sleep. Sleep Med Rev 6:55–67PubMedCrossRefGoogle Scholar
  83. Wang Y, Strahlendorf JC, Strahlendorf HK (1992) Serotonin reduces a voltage-dependent transient outward potassium current and enhances excitability of cerebellar Purkinje cells. Brain Res 571:345–349PubMedCrossRefGoogle Scholar
  84. Weiss M, Pellet J (1982a) Raphe – cerebellum interactions. I. Effects of cerebellar stimulation and harmaline administration on single unit activity of midbrain raphe neurons in the rat. Exp Brain Res 48:163–170PubMedCrossRefGoogle Scholar
  85. Weiss M, Pellet J (1982b) Raphe – cerebellum interactions. II. Effects of midbrain raphe stimulation and harmaline administration on single unit activity of cerebellar cortical cells in the rat. Exp Brain Res 48:171–176PubMedCrossRefGoogle Scholar
  86. Whitaker-Azmitia PM (2005) Behavioral and cellular consequences of increasing serotonergic activity during brain development: a role in autism? Int J Dev Neurosci 23:75–83PubMedCrossRefGoogle Scholar
  87. Whitney ER, Kemper TL, Bauman ML et al (2008) Cerebellar Purkinje cells are reduced in a subpopulation of autistic brains: a stereological experiment using calbindin-D28k. Cerebellum 7:406–416PubMedCrossRefGoogle Scholar
  88. Witter L, Rudolph S, Pressler RT et al (2016) Purkinje cell collaterals enable output signals from the cerebellar cortex to feed back to Purkinje cells and interneurons. Neuron 91:312–319PubMedPubMedCentralCrossRefGoogle Scholar
  89. Yung WH, Chan YS, Chow BK et al (2006) The role of secretin in the cerebellum. Cerebellum 5:43–48PubMedCrossRefGoogle Scholar
  90. Zhang W, Linden DJ (2006) Long-term depression at the mossy fiber-deep cerebellar nucleus synapse. J Neurosci 26:6935–6944PubMedCrossRefGoogle Scholar
  91. Zhang CZ, Zhuang QX, He YC et al (2014) 5-HT2A receptor-mediated excitation on cerebellar fastigial nucleus neurons and promotion of motor behaviors in rats. Eur J Phys 466:1259–1271CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Moritoshi Hirono
    • 1
    Email author
  • Fumihito Saitow
    • 2
  • Hidenori Suzuki
    • 2
  1. 1.Graduate School of Brain ScienceDoshisha UniversityKyotoJapan
  2. 2.Department of PharmacologyNippon Medical SchoolTokyoJapan

Section editors and affiliations

  • Donna L. Gruol
    • 1
  1. 1.Molecular and Integrative Neuroscience Department (MIND), The Scripps Research InstituteLa JollaUSA

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