文摘
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Summary
Tourette syndrome (TS) is characterized by tics, sensorimotor gating deficiencies, and abnormalities of cortico-basal ganglia circuits. A mutation in histidine decarboxylase (m>Hdcm>), the key enzyme for the biosynthesis of histamine (HA), has been implicated as a rare genetic cause. m>Hdcm> 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 m>Hdcm> mutations. HA infusion reduced striatal DA levels; in m>Hdcm> knockout mice, striatal DA was increased and the DA-regulated immediate early gene m>Fosm> was upregulated. DA D2/D3 receptor binding was altered both in mice and in humans carrying the m>Hdcm> 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.