Tourette Syndrome (TS) is a common and sometimes disabling neurodevelopmental disorder that can lead to learning and social problems in children and adults. Current treatments have some efficacy in reducing motor symptoms but are often unhelpful and are limited by side effects. New pharmacological approaches are needed. In order to develop new pharmacological treatments it is necessary to understand better the underlying neurochemical abnormalities. The pathophysiology of TS is not well understood. Data from a recent genetic study suggest that disruption in histaminergic neurotransmisson may contribute to TS: a densely affected family was found to carry a segregating nonsense mutation in the gene for histidine decarboxylase (HDC), the rate-limiting step in the biosynthesis of histamine. We have characterized behavioral and neurochemical abnormalities in mice in which the HDC gene is knocked out, recapitulating the abnormality in patients carrying the mutated allele. These mice exhibit a deficit in prepulse inhibition and an increase in stereotypical behaviors, mirroring symptoms seen in patients with TS. Preliminary neurochemical data in this animal model using in vivo microdialysis showed that these mice have reduced histamine and increased dopamine in the striatum. We now propose to broaden this behavioral and neurochemical analysis in these mice and to investigate whether drugs used in the treatment of patients with TS can mitigate the abnormalities found in these mice. We will go on to examine the effects of a new potential pharmacological treatment, a histamine H3 receptor blocker, to assess whether this drug can also mitigate the behavioral deficits. If successful, this experiment would identify an exciting new potential therapeutic target for TS. These experiments will advance our understanding of the biology of TS, establishing a new basis for future studies on the neuropathology of the condition and allowing further investigations based on the development of new therapeutic approaches. Lissandra Baldan-Ramsey, Ph.D. & Christopher Pittenger, M.D., Ph.D Yale University, New Haven, CT Award: $39,998 (Fellowship) Tourette Association of America Inc. – Research Grant Award 2012-2013