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Genetic silencing of olivocerebellar synapses causes dystonia-like behaviour in mice

Author

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  • Joshua J. White

    (Baylor College of Medicine
    Baylor College of Medicine
    Jan and Dan Duncan Neurological Research Institute of Texas Children’s Hospital)

  • Roy V. Sillitoe

    (Baylor College of Medicine
    Baylor College of Medicine
    Jan and Dan Duncan Neurological Research Institute of Texas Children’s Hospital
    Program in Developmental Biology, Baylor College of Medicine)

Abstract

Theories of cerebellar function place the inferior olive to cerebellum connection at the centre of motor behaviour. One possible implication of this is that disruption of olivocerebellar signalling could play a major role in initiating motor disease. To test this, we devised a mouse genetics approach to silence glutamatergic signalling only at olivocerebellar synapses. The resulting mice had a severe neurological condition that mimicked the early-onset twisting, stiff limbs and tremor that is observed in dystonia, a debilitating movement disease. By blocking olivocerebellar excitatory neurotransmission, we eliminated Purkinje cell complex spikes and induced aberrant cerebellar nuclear activity. Pharmacologically inhibiting the erratic output of the cerebellar nuclei in the mutant mice improved movement. Furthermore, deep brain stimulation directed to the interposed cerebellar nuclei reduced dystonia-like postures in these mice. Collectively, our data uncover a neural mechanism by which olivocerebellar dysfunction promotes motor disease phenotypes and identify the cerebellar nuclei as a therapeutic target for surgical intervention.

Suggested Citation

  • Joshua J. White & Roy V. Sillitoe, 2017. "Genetic silencing of olivocerebellar synapses causes dystonia-like behaviour in mice," Nature Communications, Nature, vol. 8(1), pages 1-16, April.
  • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14912
    DOI: 10.1038/ncomms14912
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    Cited by:

    1. Meike E. Heijden & Alejandro G. Rey Hipolito & Linda H. Kim & Dominic J. Kizek & Ross M. Perez & Tao Lin & Roy V. Sillitoe, 2023. "Glutamatergic cerebellar neurons differentially contribute to the acquisition of motor and social behaviors," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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