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Ca V 3.1 is a tremor rhythm pacemaker in the inferior olive
Open accessAbstract
The rhythmic motor pathway activation by pacemaker neurons or circuits in the brain has been proposed as the mechanism for the timing of motor coordination, and the abnormal potentiation of this mechanism may lead to a pathological tremor. Here, we show that the potentiation of Ca V 3.1 T-type Ca 2+ channels in the inferior olive contributes to the onset of the tremor in a pharmacological model of essential tremor. After administration of harmaline, 4- to 10-Hz synchronous neuronal activities arose from the IO and then propagated to cerebellar motor circuits in wild-type mice, but those rhythmic activities were absent in mice lacking Ca V 3.1 gene. Intracellular recordings in brain-stem slices revealed that the Ca V 3.1-deficient inferior olive neurons lacked the subthreshold oscillation of membrane potentials and failed to trigger 4- to 10-Hz rhythmic burst discharges in the presence of harmaline. In addition, the selective knockdown of Ca V 3.1 gene in the inferior olive by sh RNA efficiently suppressed the harmaline-induced tremor in wild-type mice. A mathematical model constructed based on data obtained from patch-clamping experiments indicated that harmaline could efficiently potentiate Ca V 3.1 channels by changing voltage-dependent responsiveness in the hyperpolarizing direction. Thus, Ca V 3.1 is a molecular pacemaker substrate for intrinsic neuronal oscillations of inferior olive neurons, and the potentiation of this mechanism can be considered as a pathological cause of essential tremor.
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“Moreover, T-type calcium channels are a powerful mechanism by which the IO regulates cerebellar output [269].”
From Consensus Paper: Pathological Role of the Cerebellum in Autism (2012) · cites this paper as [269]
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“In this frame, oscillatory activity would not originate exclusively in the cerebellar cortex but would be generated in the whole motor network through cerebello-thalamocortical (CTC) pathways [3] including the inferior olive [4].”
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“…olive in tremor generation in the literature comes from animal models that suggest the inferior olive to function as an intrinsic pacemaker (Long et al., 2002) and the suggestion that the inferior olive would be prone to intrinsic calcium channel-dependent neuronal oscillations (Park et al., 2010).”
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Self-citationInhibitory Basal Ganglia Inputs Induce Excitatory Motor Signals in the Thalamus
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“1 expressed in the inferior olive was shown to be associated with tremor [30].”
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“In the central nervous system, the gap junctions of the inferior olive contribute to a subthreshold oscillation of ~10 Hz (Leznik and Llinás, 2005), which becomes relevant to the pathological tremor produced by harmaline (Park et al., 2010).”
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Climbing Fiber Burst Size and Olivary Sub-threshold Oscillations in a Network Setting
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“Calcium currents are the cause of the IO cells’ typical spike ADP and low-threshold voltage-dependent calcium ion channels have been shown to be important in the generation of the IO cells’ STOs [20],[34].”
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“Understanding the physiological role of T-type calcium channels has been for long time limited by the lack of selective pharmacological compounds (Perez-Reyes, 2003), but new T-type antagonists have recently been reported (Barrow et al., 2007; Shipe et al., 2008; Yang et al., 2008).”
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“02 mS∙cm(2) to mimic the experimental conditions reported in ref (6), while the intensity of IOC was set to 2 pA for all ION neurons.”
BackgroundMethodOlivary subthreshold oscillations and burst activity revisited
Bazzigaluppi, P., Gruijl, J. R. D., van der Giessen, R. S., Khosrovani, S., Zeeuw, C. I. D., & de Jeu, M. T. G. (2012) · Frontiers in Neural Circuits · doi:10.3389/fncir.2012.00091 · Cited by 67
“The drug is known to cause an 8–14 Hz tremor in mice (Wang and Fowler, 2001) and it is assumed to act by modulating the rhythm-generating ionic currents of IO cells (Llinás and Yarom, 1986; Choi et al., 2010; Park et al., 2010).”
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Louis, E. D., Babij, R., Cortes, E. P., Vonsattel, J., & Faust, P. L. (2013) · Movement Disorders · doi:10.1002/mds.25400 · Cited by 66
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Self-citationProperties of the Nucleo-Olivary Pathway: An In Vivo Whole-Cell Patch Clamp Study
Bazzigaluppi, P., Ruigrok, T. J. H., Saisan, P. A., Zeeuw, C. I. D., & de Jeu, M. T. G. (2012) · PLoS ONE · doi:10.1371/journal.pone.0046360 · Cited by 61
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Minimal alterations in T‐type calcium channel gating markedly modify physiological firing dynamics
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“…in the T current model described here are well within the range of the reported modifications of T currents by endogenous ligands and/or intracellular pathways (Chemin et al. 2001c; Iftinca et al. 2007; Traboulsie et al. 2007; Barbara et al. 2009; Hildebrand et al. 2009; Park et al. 2010).”
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“The tremorogenic olivocerebellar oscillation produced by harmaline in laboratory animals has long been viewed as animal model of ET [49, 50], but conclusive evidence of olivary dysfunction in patients with ET is lacking.”
Pathogenesis of severe ataxia and tremor without the typical signs of neurodegeneration
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Essential Tremor, the Cerebellum, and Motor Timing: Towards Integrating Them into One Complex Entity
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“Importantly, these shRNAis were functionally validated (Park et al., 2010; Figure S5B).”
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“Harmaline hyperpolarizes olivary neurons and induces action potentials which extend to the cerebellar cortex and manifest as tremor [86, 87].”
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BackgroundT-Type Calcium Channel as a New Therapeutic Target for Tremor
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“A recent report by Park et al. [ 31 ]s howed that harmaline-induced tremor is suppressed in mice with a selective knockdown of the CaV3.1 gene in the inferior olive, successfully showing that T-type Ca channels are actually involved in the tremor-generating mechanisms underlying harmaline-induced tremors.”
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Linking Essential Tremor to the Cerebellum—Animal Model Evidence
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“Harmaline's mechanism of action may involve complex effects on T-type calcium channels [8] or alternatively may trigger tremor by attenuating”
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“1 subunit of TTCCs supports the change from tonic to burst discharge of GABAergic neurons in this nucleus (Park et al., 2010a).”
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“, neuronal oscillations that occur as a result of intrinsic membrane potential fluctuations but which are below the voltage threshold required to cause a neuron to fire) are dependent on TTCC conductance(148) and closely associated with generation of tremor rhythm, and have been shown to be amplified in IO neurons fol…”
BackgroundAtaxic phenotype with altered CaV3.1 channel property in a mouse model for spinocerebellar ataxia 42
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“1 T-type Ca 2+) (Park et al., 2010).”
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“Tremor-related oscillations in the olivocerebellar pathway are key abnormalities underlying ET and trigger onset of tremor-related rhythms (38).”
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“Regardless of whether ET is a neurodegenerative disease affecting PC [51], or the result of pacemaking neurons in the inferior olive [48–50], these structures are controlled by GABAergic connections [52].”
BackgroundDual role of T-type calcium channels in anxiety-related behavior
Kaur, S., Маслов, Л. Н., Singh, N., & Jaggi, A. S. (2019) · Journal of Basic and Clinical Physiology and Pharmacology · doi:10.1515/jbcpp-2019-0067 · Cited by 17
The potential roles of T-type Ca2+ channels in motor coordination
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“Once the neural circuits are defined, then isoformspecific knockdowns of T-type Ca2+ channels (Park et al., 2010) can be applied to identified circuits.”
BackgroundInfluentialSelf-citationHypertrophic Olivary Degeneration Does Not Reduce Essential Tremor
Elkouzi, A., Kattah, J. C., & Elble, R. J. (2015) · Movement Disorders Clinical Practice · doi:10.1002/mdc3.12275 · Cited by 16
“The inferior olive is postulated to play a critical role in the generation of essential tremor (ET) and palatal tremor.(1) The olivary hypothesis of ET stems mainly from the harmaline animal model, in which action tremor resembling ET is caused by harmaline-induced olivary oscillation.”
BackgroundNew Perspectives for Computer-Aided Discrimination of Parkinson’s Disease and Essential Tremor
Povalej, P., Gallego, J. Á., Romero, J. P., Glaser, V., Rocón, E., Benito‐León, J., Bermejo‐Pareja, F., Posada, I. J., & Holobar, A. (2017) · Complexity · doi:10.1155/2017/4327175 · Cited by 16
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An Update on the Neurochemistry of Essential Tremor
Jiménez‐Jiménez, F. J., Alonso‐Navarro, H., García‐Martín, E., & Agúndez, J. A. G. (2018) · Current Medicinal Chemistry · doi:10.2174/0929867325666181112094330 · Cited by 16
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Heterogeneity of tremor mechanisms assessed by tremor-related cortical potential in mice
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“8A) (Park et al., 2010).”
BackgroundMethodInfluentialHarmaline Attenuates Voltage - Sensitive Ca2+ Currents in Neurons of the Inferior Olive
Zhan, X., & Graf, W. M. (2012) · Journal of Pharmacy & Pharmaceutical Sciences · doi:10.18433/j3w595 · Cited by 15
“The concentrations we investigated for both voltage and current clamp recording are larger than that Park et al used (0.001~ 0.1 mM) for voltage clamp, but slightly smaller than that used for current clamp recording (0.1 mg/ml or 0.35 mM) (17).”
BackgroundMethodResultInfluentialOculopalatal Tremor: Variations on a Theme by Guillain and Mollaret
Jang, L., & Borruat, F. (2014) · European Neurology · doi:10.1159/000360531 · Cited by 14
Non-invasive Central and Peripheral Stimulation: New Hope for Essential Tremor?
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D’Apolito, M., Ceccarini, C., Savino, R., Adipietro, I., di Bari, I., Santacroce, R., Curcetti, M., D’Andrea, G., Croce, A.-I., Cesarano, C., et al. (2023) · Genes · doi:10.3390/genes14071380 · Cited by 13
“1 gene expression in the inferior olive neurons efficiently suppressed harmaline-induced tremor in wild-type mice [9].”
BackgroundKunisawa, N., Shimizu, S., Kato, M., Iha, H. A., Iwai, C., Hashimura, M., Ogawa, M., Kawaji, S., Kawakita, K., Abé, K., et al. (2018) · Journal of Pharmacological Sciences · doi:10.1016/j.jphs.2018.05.007 · Cited by 13
Is the inferior olive central to essential tremor? Yes
Lang, E. J., & Handforth, A. (2022) · International review of neurobiology · doi:10.1016/bs.irn.2022.02.009 · Cited by 13
Bazzigaluppi, P., & de Jeu, M. T. G. (2016) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2016.00192 · Cited by 12
“1 -/- mutant mice (Choi et al., 2010; Park et al., 2010).”
BackgroundCharacteristics of Tremor Induced by Lesions of the Cerebellum
Kovács, A., Kiss, M., Pinter, N. K., Szirmai, I. G., & Kamondi, A. (2019) · The Cerebellum · doi:10.1007/s12311-019-01027-3 · Cited by 12
“1 channels’ responsiveness, or the inferior olive might also be needed for sustained tremor [8].”
BackgroundEssential Tremor—Do We Have Better Therapeutics? A Review of Recent Advances and Future Directions
Shetty, N. (2022) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-022-01185-8 · Cited by 10
Post-Inhibitory Rebound Firing of Dorsal Root Ganglia Neurons
Zhu, T., Wei, S., & Wang, Y. (2022) · Journal of Pain Research · doi:10.2147/jpr.s370335 · Cited by 11
Targeting the T-type calcium channel Cav3.2 in GABAergic arcuate nucleus neurons to treat obesity
Feng, B. C., Harms, J., Patel, N., Ye, H., Luo, P., Irizarry, V. C. T., Vidrine, J., Coulter, A. A., Rebello, C. J., Yu, S., et al. (2021) · Molecular Metabolism · doi:10.1016/j.molmet.2021.101391 · Cited by 11
Shukla, A. W. (2022) · International review of neurobiology · doi:10.1016/bs.irn.2022.02.008 · Cited by 12
Mechanisms and Pharmacotherapy for Ethanol-Responsive Movement Disorders
Wu, J., Tang, H., Chen, S., & Cao, L. H. (2020) · Frontiers in Neurology · doi:10.3389/fneur.2020.00892 · Cited by 11
Gong, Y., Liu, R., Zha, H.-J., Dong, D., Lu, N., Yan, H., Wan, L.-S., & Nian, Y. (2023) · Angewandte Chemie International Edition · doi:10.1002/anie.202313461 · Cited by 10
Enhancing GABA inhibition is the next generation of medications for essential tremor
Ondo, W. G. (2022) · International review of neurobiology · doi:10.1016/bs.irn.2022.02.007 · Cited by 9
Mukherjee, A., & Pandey, S. (2025) · Movement Disorders Clinical Practice · doi:10.1002/mdc3.70147 · Cited by 8
Agmatine has beneficial effect on harmaline-induced essential tremor in rat
Akman, Ö., Utkan, T., Arıcıoğlu, F., Güllü, M. K., Ateş, N., & Karson, A. (2021) · Neuroscience Letters · doi:10.1016/j.neulet.2021.135881 · Cited by 8
Mapping BOLD Activation by Pharmacologically Evoked Tremor in Swine
Lee, J., Jo, H. J., Kim, I., Lee, J., Min, H.-K. P., In, M., Knight, E. J., & Chang, S.-Y. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00985 · Cited by 8
Implications of Electrical Synapse Plasticity in the Inferior Olive
Welsh, J. P., & Turecek, J. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-803471-2.00012-6 · Cited by 7
Thalamo-cortical network is associated with harmaline-induced tremor in rodent model
Lee, J., Kim, J., Cortez, J., & Chang, S.-Y. (2022) · Experimental Neurology · doi:10.1016/j.expneurol.2022.114210 · Cited by 7
Targeting the fundamentals for tremors: the frequency and amplitude coding in essential tremor
Pan, M. (2025) · Journal of Biomedical Science · doi:10.1186/s12929-024-01112-8 · Cited by 10
Is essential tremor a disorder of GABA dysfunction? No
Bellows, S. T., & Shahed, J. J. (2022) · International review of neurobiology · doi:10.1016/bs.irn.2022.02.006 · Cited by 7
Overcoming Depression by Inhibition of Neural Burst Firing
Kim, D., Cheong, E., & Shin, H. (2018) · Neuron · doi:10.1016/j.neuron.2018.05.032 · Cited by 7
Self-citationDeep Brain Stimulation for Essential Tremor
Morigaki, R., & Goto, S. (2015) · Springer eBooks · doi:10.1007/978-3-319-08476-3_11 · Cited by 92
Sharifi, S., Luft, F., de Boer, L., Buijink, A. W. G., Mugge, W., Schouten, A. C., Heida, T., Bour, L. J., & van Rootselaar, A. (2022) · NeuroImage · doi:10.1016/j.neuroimage.2022.119554 · Cited by 6
Hara, N., Morino, H., Matsuda, Y., Satoh, K., Hashimoto, K., Maruyama, H., & Kawakami, H. (2020) · Molecular Brain · doi:10.1186/s13041-020-00700-7 · Cited by 6
“1 is highly expressed in the inferior olive and cerebellum and is involved in the generation of tremorrelated rhythms [11].”
BackgroundCerebellar nuclei neurons display aberrant oscillations during harmaline-induced tremor
Baumel, Y., Yamin, H. G., & Cohen, D. (2021) · Heliyon · doi:10.1016/j.heliyon.2021.e08119 · Cited by 6
“Harmaline induces network oscillations at about 10 Hz, originating in the IO and spreading into the cerebellar cortex and the CN (Milner et al., 1995; Llinas and Volkind, 1973; Park et al., 2010).”
BackgroundTreatment of intractable resting tremor of spinocerebellar ataxia 42 with zonisamide
Hara, N., Nezu, T., Kobatake, K., Morino, H., Kawakami, H., & Maruyama, H. (2018) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2018.11.013 · Cited by 6
Imaging Subthreshold Voltage Oscillation With Cellular Resolution in the Inferior Olive in vitro
Dorgans, K., Kühn, B., & Uusisaari, M. Y. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.607843 · Cited by 6
Is inferior olive central to the pathophysiology of essential tremor? No
Manto, M. U. (2022) · International review of neurobiology · doi:10.1016/bs.irn.2022.02.010 · Cited by 6
Harmaline toxicity on dorsal striatal neurons and its role in tremor
Zhan, X., Do, L. V., Zou, L. B., Zhan, R. S., Jones, M., Nawaz, S., & Manaye, K. F. (2023) · NeuroToxicology · doi:10.1016/j.neuro.2023.10.005 · Cited by 5
von der Gablentz, J., Sprenger, A., Heldmann, M., Münte, T. F., & Helmchen, C. (2013) · Journal of Neurology · doi:10.1007/s00415-013-7059-z · Cited by 5
Metadata
- Authors
- Park, Y.-G., Park, H.-Y., Lee, C. J., Choi, S., Jo, S., Choi, H., Kim, Y.-H., Shin, H.-S., Llinas, R. R., & Kim, D.
- Affiliations
- Korea Advanced Institute of Science and Technology (KR)
- Korea Institute of Science and Technology (KR)
- New York University (US)
- Department of Physiology and Neuroscience, New York University School of Medicine, New York, NY 10016; and
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-05-24
- Volume
- 107
- Issue
- 23
- Pages
- 10731-10736
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2890811
- OpenAlex
- W2075318347
- Cited by
- 142
- References
- 45
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 3 · 2023: 8 · 2022: 14 · 2021: 9 · 2020: 8 · 2019: 15 · 2018: 7 · 2017: 8 · 2016: 2 · 2015: 12 · 2014: 12 · 2013: 9 · 2012: 16
- FWCI
- 6.48
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Education, Science and Technology
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (NS 13742, P01NS013742)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Deep Brain Stimulation and Movement Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- Cav3.1, T-type calcium channels, inferior olive, essential tremor, pathological tremor, pacemaker neurons, harmaline, neural oscillations, shRNA knockdown
- MeSH terms
- Animals, Cell Line, Disease Models, Animal, Harmaline, Humans, Male, Mice, Inbred C57BL, Olivary Nucleus, Tremor, Mice, Knockout, Calcium Channels, T-Type, RNA Interference, Mice
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