title: Ablation of fast-spiking interneurons in the dorsal striatum, recapitulating abnormalities seen post-mortem in Tourette syndrome, produces anxiety and elevated grooming.
abstract: Tic disorders, including Tourette syndrome (TS), are thought to involve pathology of cortico-basal ganglia loops, but their pathology is not well understood. Post-mortem studies have shown a reduced number of several populations of striatal interneurons, including the parvalbumin-expressing fast-spiking interneurons (FSIs), in individuals with severe, refractory TS. We tested the causal role of this interneuronal deficit by recapitulating it in an otherwise normal adult mouse using a combination transgenic-viral cell ablation approach. FSIs were reduced bilaterally by ∼40%, paralleling the deficit found post-mortem. This did not produce spontaneous stereotypies or tic-like movements, but there was increased stereotypic grooming after acute stress in two validated paradigms. Stereotypy after amphetamine, in contrast, was not elevated. FSI ablation also led to increased anxiety-like behavior in the elevated plus maze, but not to alterations in motor learning on the rotorod or to alterations in prepulse inhibition, a measure of sensorimotor gating. These findings indicate that a striatal FSI deficit can produce stress-triggered repetitive movements and anxiety. These repetitive movements may recapitulate aspects of the pathophysiology of tic disorders.
authors.affiliation: Department of Psychiatry, Yale University, New Haven, CT, United States.
authors.forename: M
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Psychiatry, Yale University, New Haven, CT, United States.
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Psychiatry, Yale University, New Haven, CT, United States; Department of Psychology, Yale University, New Haven, CT, United States; Child Study Center, Yale University, New Haven, CT, United States; Interdepartmental Neuroscience Program, Yale University, New Haven, CT, United States. Electronic address: Christopher.pittenger@yale.edu.
authors.forename: C
authors.initials: C
authors.lastname: Pittenger
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001007:Anxiety / Q000473:pathology / Q000503:physiopathology*; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003213:Conditioning, Psychological / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D005239:Fear / Q000502:physiology; D006120:Grooming / Q000187:drug effects / Q000502:physiology*; D007395:Interneurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D010320:Parvalbumins / Q000378:metabolism; D065808:Prepulse Inhibition / Q000502:physiology; D013239:Stereotyped Behavior / Q000187:drug effects / Q000502:physiology*; D005879:Tourette Syndrome / Q000473:pathology* / Q000503:physiopathology
chemical_list: D000697:Central Nervous System Stimulants; D010320:Parvalbumins; D000661:Amphetamine
keywords: Tourette syndrome; basal ganglia; fast-spiking interneurons; parvalbumin; tics