title: Targeted ablation of cholinergic interneurons in the dorsolateral striatum produces behavioral manifestations of Tourette syndrome.
abstract: Gilles de la Tourette syndrome (TS) is characterized by tics, which are transiently worsened by stress, acute administration of dopaminergic drugs, and by subtle deficits in motor coordination and sensorimotor gating. It represents the most severe end of a spectrum of tic disorders that, in aggregate, affect ∼ 5% of the population. Available treatments are frequently inadequate, and the pathophysiology is poorly understood. Postmortem studies have revealed a reduction in specific striatal interneurons, including the large cholinergic interneurons, in severe disease. We tested the hypothesis that this deficit is sufficient to produce aspects of the phenomenology of TS, using a strategy for targeted, specific cell ablation in mice. We achieved ∼ 50% ablation of the cholinergic interneurons of the striatum, recapitulating the deficit observed in patients postmortem, without any effect on GABAergic markers or on parvalbumin-expressing fast-spiking interneurons. Interneuron ablation in the dorsolateral striatum (DLS), corresponding roughly to the human putamen, led to tic-like stereotypies after either acute stress or d-amphetamine challenge; ablation in the dorsomedial striatum, in contrast, did not. DLS interneuron ablation also led to a deficit in coordination on the rotorod, but not to any abnormalities in prepulse inhibition, a measure of sensorimotor gating. These results support the causal sufficiency of cholinergic interneuron deficits in the DLS to produce some, but not all, of the characteristic symptoms of TS.
authors.affiliation: Departments of Psychiatry.
authors.forename: Meiyu
authors.initials: M
authors.lastname: Xu
authors.affiliation: Departments of Psychiatry.
authors.forename: Andrew
authors.initials: A
authors.lastname: Kobets
authors.affiliation: Departments of Psychiatry.
authors.forename: Jung-Chieh
authors.initials: JC
authors.lastname: Du
authors.affiliation: Child Study Center and.
authors.forename: Jessica
authors.initials: J
authors.lastname: Lennington
authors.affiliation: Departments of Psychiatry.
authors.forename: Lina
authors.initials: L
authors.lastname: Li
authors.affiliation: Departments of Psychiatry.
authors.forename: Mounira
authors.initials: M
authors.lastname: Banasr
authors.affiliation: Departments of Psychiatry, Pharmacology, Interdepartmental Neuroscience Program, Yale University, New Haven, CT 06519.
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Duman
authors.affiliation: Child Study Center and Interdepartmental Neuroscience Program, Yale University, New Haven, CT 06519 Neurobiology.
authors.forename: Flora M
authors.initials: FM
authors.lastname: Vaccarino
authors.affiliation: Departments of Psychiatry, Interdepartmental Neuroscience Program, Yale University, New Haven, CT 06519 Neurobiology.
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: DiLeone
authors.affiliation: Departments of Psychiatry, Child Study Center and Interdepartmental Neuroscience Program, Yale University, New Haven, CT 06519 Psychology, and the christopher.pittenger@yale.edu.
authors.forename: Christopher
authors.initials: C
authors.lastname: Pittenger
mesh_terms: D000200:Action Potentials; D000818:Animals; D002795:Choline O-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D003342:Corpus Striatum / Q000473:pathology*; D004167:Diphtheria Toxin / Q000494:pharmacology*; D007395:Interneurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D011950:Receptors, Cholinergic / Q000378:metabolism*; D005879:Tourette Syndrome / Q000473:pathology* / Q000523:psychology
chemical_list: D004167:Diphtheria Toxin; D011950:Receptors, Cholinergic; D002795:Choline O-Acetyltransferase
keywords: Tourette sydrome; acetylcholine; animal models; basal ganglia; interneurons