title: Genetic silencing of olivocerebellar synapses causes dystonia-like behaviour in mice.
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.
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.|Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA.|Jan and Dan Duncan Neurological Research Institute of Texas Children's Hospital, 1250 Moursund Street, Suite 1325, Houston, Texas 77030, USA.
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: White
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.|Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA.|Jan and Dan Duncan Neurological Research Institute of Texas Children's Hospital, 1250 Moursund Street, Suite 1325, Houston, Texas 77030, USA.|Program in Developmental Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Roy V
authors.initials: RV
authors.lastname: Sillitoe
mesh_terms: D000818:Animals; D002529:Cerebellar Nuclei / Q000378:metabolism*; D002531:Cerebellum / Q000378:metabolism; D046690:Deep Brain Stimulation; D004195:Disease Models, Animal; D004421:Dystonia / Q000378:metabolism*; D000075423:Gene Drive Technology; D018698:Glutamic Acid / Q000378:metabolism*; D051379:Mice; D009434:Neural Pathways; D009847:Olivary Nucleus / Q000378:metabolism*; D011689:Purkinje Cells / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission; D014157:Transcription Factors / Q000235:genetics; D050599:Vesicular Glutamate Transport Protein 2 / Q000235:genetics
chemical_list: C493477:Slc17a6 protein, mouse; D014157:Transcription Factors; D050599:Vesicular Glutamate Transport Protein 2; C062602:transcription factor PTF1; D018698:Glutamic Acid