The pathophysiology of Tourette syndrome (TS) is not well understood. The recent cloning of a dominant-acting nonsense mutation in the histidine decarboxylase (HDC) gene suggests that abnormalities in histaminergic modulation may contribute to TS symptoms. We have found that mice lacking one or both HDC alleles exhibit stereotypy (which is mitigated by haloperidol pretreatment), have a deficit in prepulse inhibition, and also show neurochemical abnormalities in the basal ganglia circuitry that parallel those found in patients. This new mouse model, with construct, face, and predictive validity represents an unparalleled tool for the further elucidation of TS pathophysiology. Immune dysregulation may contribute to TS. TS patients have a decreased number of CD4+ CD25+ CD69- regulatory T cells (T-regs). These cells are potent inhibitors of self-reactive CD4 and CD8 T lymphocytes that are reduced in certain autoimmune diseases. Furthermore, CCL2/MCP-1, a key regulator of microglia – the brain’s endogenous phagocytes – is elevated in the basal ganglia of TS patients, as is the T-cell derived cytokine IL-2. Recent data identify histamine as an important modulator of microglial activity. Histamine triggers microglial motility in vitro via H4 receptors. Conversely, H4 activation counteracts LPS-induced microglia migration and IL-1beta production. Histamine infusion into the striatum or the substantia nigra results in microglial activation and neurodegeneration. We hypothesize that histamine deficiency in TS patients carrying the HDC mutation and in our mouse model may lead to microglial abnormalities that contribute to TS symptomatology. We propose to test this relationship in the HDC mouse model by: 1. Characterizing abnormalities in microglia in HDC-KO mice and heterozygotes. We will assay microglial number, activation, morphology, and expression of key regulatory proteins. 2. Reverse microglia alterations, and the documented behavioral and neurochemical phenotypes, in HDC-KO mice, using virus-mediated rescue of neuronal histamine production. This will confirm the causal role of histamine deficiency in key disease-related phenotypes. Luciana R. Frick, Ph.D. & Christopher Pittenger, M.D., Ph.D. Yale University School of Medicine, New Haven, CT Award: $40,000 (Fellowship) Tourette Association of America Inc. – Research Grant Award 2013-2014