title: Corticostriatal interactions in the generation of tic-like behaviors after local striatal disinhibition.
abstract: The pathophysiology of the tics that define Gilles de la Tourette syndrome (TS) is not well understood. Local disinhibition within the striatum has been hypothesized to play a pathogenic role. In support of this, experimental disinhibition by local antagonism of GABA-A receptors within the striatum produces tic-like phenomenology in monkey and rat. We replicated this effect in mice via local picrotoxin infusion into the dorsal striatum. Infusion of picrotoxin into sensorimotor cortex produced similar movements, accompanied by signs of behavioral activation; higher-dose picrotoxin in the cortex produced seizures. Striatal inhibition with local muscimol completely abolished tic-like movements after either striatal or cortical picrotoxin, confirming their dependence on the striatal circuitry; in contrast, cortical muscimol attenuated but did not abolish movements produced by striatal picrotoxin. Striatal glutamate blockade eliminated tic-like movements after striatal picrotoxin, indicating that glutamatergic afferents are critical for their generation. These studies replicate and extend previous work in monkey and rat, providing additional validation for the local disinhibition model of tic generation. Our results reveal a key role for corticostriatal glutamatergic afferents in the generation of tic-like movements in this model.
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Pogorelov
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, USA.
authors.forename: Meiyu
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Neurology, Yale University School of Medicine, USA.
authors.forename: Haleigh R
authors.initials: HR
authors.lastname: Smith
authors.affiliation: Department of Neurology, Yale University School of Medicine, USA.
authors.forename: Gordon F
authors.initials: GF
authors.lastname: Buchanan
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, USA; Department of Psychology, Yale University School of Medicine, USA; Department of Child Study Center, Yale University School of Medicine, USA; Interdepartmental Neuroscience Program, Yale University School of Medicine, USA. Electronic address: Christopher.pittenger@yale.edu.
authors.forename: Christopher
authors.initials: C
authors.lastname: Pittenger
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000503:physiopathology*; D004569:Electroencephalography / Q000187:drug effects / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009434:Neural Pathways / Q000187:drug effects / Q000503:physiopathology; D010852:Picrotoxin / Q000633:toxicity; D066191:Sensorimotor Cortex / Q000187:drug effects / Q000503:physiopathology*; D020323:Tics / Q000139:chemically induced / Q000503:physiopathology*
chemical_list: D010852:Picrotoxin
keywords: Animal model; Basal ganglia; Movement disorders; Tic; Tourette syndrome