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

Lissandra Castellan Baldan, Kyle A Williams, Jean-Dominique Gallezot, Vladimir Pogorelov, Maximiliano Rapanelli, Michael Crowley, George M Anderson, Erin Loring, Roxanne Gorczyca, Eileen Billingslea, Suzanne Wasylink, Kaitlyn E Panza, A Gulhan Ercan-Sencicek, 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 Pittenger

Index: Neuron 81(1) , 77-90, (2014)

Full Text: HTML

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. Copyright © 2014 Elsevier Inc. All rights reserved.