Histidine decarboxylase deficiency causes tourette syndrome: parallel findings in humans and mice

Neuron. 2014 Jan 8;81(1):77-90. doi: 10.1016/j.neuron.2013.10.052.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Adolescent
  • Adult
  • Amphetamine
  • Animals
  • Brain / diagnostic imaging
  • Brain / enzymology*
  • Brain / pathology
  • Child
  • Dopamine Agonists / therapeutic use
  • Dopamine Antagonists / pharmacokinetics
  • Exploratory Behavior / physiology
  • Female
  • Histidine Decarboxylase / deficiency*
  • Histidine Decarboxylase / genetics
  • Humans
  • Male
  • Maze Learning / physiology
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Mutation / genetics*
  • Oxazines
  • Raclopride / pharmacokinetics
  • Radionuclide Imaging
  • Stereotyped Behavior / drug effects
  • Stereotyped Behavior / physiology
  • Time Factors
  • Tourette Syndrome / diagnostic imaging
  • Tourette Syndrome / enzymology*
  • Tourette Syndrome / genetics*
  • Tourette Syndrome / physiopathology
  • Tryptophan / genetics
  • Young Adult


  • Dopamine Agonists
  • Dopamine Antagonists
  • Oxazines
  • naxagolide
  • Raclopride
  • Tryptophan
  • Amphetamine
  • Histidine Decarboxylase