Histidine Decarboxylase Deficiency Causes Tourette Syndrome: Parallel Findings in Humans and Mice

• DOI: 10.1016/j.neuron.2013.10.052
• Publication Date: 2014-01-08T15:31:13Z
• Authors: Lissandra Castell...; Kyle A. Williams; Jean-Dominique Ga...; Vladimir Pogorelov; Maximiliano Rapan...; Michael Crowley; George M. Anderson; Erin Loring; Roxanne Gorczyca; Eileen Billingslea; Suzanne Wasylink; Kaitlyn E. Panza; A. Gulhan Ercan-S...; Kuakarun Krusong; Bennett L. Leventhal; Hiroshi Ohtsu; Michael H. Bloch; Zoë A. Hughes; John H. Krystal; Linda Mayes; Ivan de Araujo; Yu-Shin Ding; Matthew W. State; Christopher Pitte...
• Keywords: Adult; Male; Time Factors; Adolescent; Knockout; Neuroscience(all); Biological Psychology; Neurodegenerative; Histidine Decarboxylase; Young Adult; Mice; Oxazines; Genetics; Psychology; 2.1 Biological and endogenous factors; Animals; Humans; Aetiology; Radionuclide Imaging; Child; Maze Learning; Mice, Knockout; Neurology & Neurosurgery; Biomedical and Clinical Sciences; Neurosciences; Tryptophan; Brain; Pharmacology and Pharmaceutical Sciences; Middle Aged; Brain Disorders; 3. Good health; Amphetamine; Raclopride; Dopamine Agonists; Mutation; Exploratory Behavior; Biological psychology; Dopamine Antagonists; Cognitive Sciences; Female; Stereotyped Behavior; Tourette Syndrome

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.