title: Histidine decarboxylase deficiency causes tourette syndrome: parallel findings in humans and mice.
abstract: Tourette syndrome (TS) is characterized by tics, sensorimotor gating deficiencies, and abnormalities of cortico-basal ganglia circuits. A mutation in histidine decarboxylase (Hdc), the key enzyme for the biosynthesis of histamine (HA), has been implicated as a rare genetic cause. Hdc knockout mice exhibited potentiated tic-like stereotypies, recapitulating core phenomenology of TS; these were mitigated by the dopamine (DA) D2 antagonist haloperidol, a proven pharmacotherapy, and by HA infusion into the brain. Prepulse inhibition was impaired in both mice and humans carrying Hdc mutations. HA infusion reduced striatal DA levels; in Hdc knockout mice, striatal DA was increased and the DA-regulated immediate early gene Fos was upregulated. DA D2/D3 receptor binding was altered both in mice and in humans carrying the Hdc mutation. These data confirm histidine decarboxylase deficiency as a rare cause of TS and identify HA-DA interactions in the basal ganglia as an important locus of pathology.
authors.affiliation: Department of Psychiatry, Yale University School of Medicine.
authors.forename: Lissandra Castellan
authors.initials: LC
authors.lastname: Baldan
authors.affiliation: Department of Psychiatry, Yale University School of Medicine.|Department of Child Study Center, Yale University School of Medicine.
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Williams
authors.affiliation: Department of Diagnostic Radiology, Yale University School of Medicine.
authors.forename: Jean-Dominique
authors.initials: JD
authors.lastname: Gallezot
authors.affiliation: Department of Psychiatry, Yale University School of Medicine.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Pogorelov
authors.affiliation: Department of Psychiatry, Yale University School of Medicine.
authors.forename: Maximiliano
authors.initials: M
authors.lastname: Rapanelli
authors.affiliation: Department of Child Study Center, Yale University School of Medicine.
authors.forename: Michael
authors.initials: M
authors.lastname: Crowley
authors.affiliation: Department of Child Study Center, Yale University School of Medicine.|Department of Laboratory Medicine, Yale University School of Medicine.
authors.forename: George M
authors.initials: GM
authors.lastname: Anderson
authors.affiliation: Department of Child Study Center, Yale University School of Medicine.|Department of Genetics, Yale University School of Medicine.|Department of Program on Neurogenetics, Yale University School of Medicine.
authors.forename: Erin
authors.initials: E
authors.lastname: Loring
authors.affiliation: Neuroscience Research Unit, Pfizer, Inc., Cambridge, MA.
authors.forename: Roxanne
authors.initials: R
authors.lastname: Gorczyca
authors.affiliation: Department of Psychiatry, Yale University School of Medicine.
authors.forename: Eileen
authors.initials: E
authors.lastname: Billingslea
authors.affiliation: Department of Psychiatry, Yale University School of Medicine.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Wasylink
authors.affiliation: Department of Child Study Center, Yale University School of Medicine.
authors.forename: Kaitlyn E
authors.initials: KE
authors.lastname: Panza
authors.affiliation: Department of Child Study Center, Yale University School of Medicine.|Department of Genetics, Yale University School of Medicine.
authors.forename: A Gulhan
authors.initials: AG
authors.lastname: Ercan-Sencicek
authors.affiliation: Department of Psychiatry, Yale University School of Medicine.|Dept. of Biochem., Faculty of Science, Chulalongkorn Univ., Bangkok, Thailand.
authors.forename: Kuakarun
authors.initials: K
authors.lastname: Krusong
authors.affiliation: Nathan S. Kline Institute for Psychiatric Research.|New York University Dept of Child and Adolescent Psychiatry.
authors.forename: Bennett L
authors.initials: BL
authors.lastname: Leventhal
authors.affiliation: Tohoku University, Graduate School of Engineering, Sendai, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohtsu
authors.affiliation: Department of Psychiatry, Yale University School of Medicine.|Department of Child Study Center, Yale University School of Medicine.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Bloch
authors.affiliation: Neuroscience Research Unit, Pfizer, Inc., Cambridge, MA.
authors.forename: Zoë A
authors.initials: ZA
authors.lastname: Hughes
authors.affiliation: Department of Psychiatry, Yale University School of Medicine.
authors.forename: John H
authors.initials: JH
authors.lastname: Krystal
authors.affiliation: Department of Psychiatry, Yale University School of Medicine.|Department of Child Study Center, Yale University School of Medicine.|Department of Pediatrics, Yale University School of Medicine.|Department of Psychology, Yale University School of Medicine.
authors.forename: Linda
authors.initials: L
authors.lastname: Mayes
authors.affiliation: Department of Psychiatry, Yale University School of Medicine.|John B. Pierce Laboratory, New Haven, CT.
authors.forename: Ivan
authors.initials: I
authors.lastname: de Araujo
authors.affiliation: Department of Diagnostic Radiology, Yale University School of Medicine.
authors.forename: Yu-Shin
authors.initials: YS
authors.lastname: Ding
authors.affiliation: Department of Psychiatry, Yale University School of Medicine.|Department of Child Study Center, Yale University School of Medicine.|Department of Genetics, Yale University School of Medicine.|Department of Program on Neurogenetics, Yale University School of Medicine.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: State
authors.affiliation: Department of Psychiatry, Yale University School of Medicine.|Department of Child Study Center, Yale University School of Medicine.|Department of Psychology, Yale University School of Medicine.|Integrated Neuroscience Research Program; New Haven, CT 06520.
authors.forename: Christopher
authors.initials: C
authors.lastname: Pittenger
mesh_terms: D000293:Adolescent; D000328:Adult; D000661:Amphetamine; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000473:pathology; D002648:Child; D018491:Dopamine Agonists / Q000627:therapeutic use; D018492:Dopamine Antagonists / Q000493:pharmacokinetics; D005106:Exploratory Behavior / Q000502:physiology; D005260:Female; D006640:Histidine Decarboxylase / Q000172:deficiency* / Q000235:genetics; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010078:Oxazines; D020891:Raclopride / Q000493:pharmacokinetics; D011877:Radionuclide Imaging; D013239:Stereotyped Behavior / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D005879:Tourette Syndrome / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D014364:Tryptophan / Q000235:genetics; D055815:Young Adult
chemical_list: D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D010078:Oxazines; C042631:naxagolide; D020891:Raclopride; D014364:Tryptophan; D000661:Amphetamine; D006640:Histidine Decarboxylase