{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T20:09:57Z","timestamp":1789416597725,"version":"build-2803163510"},"reference-count":72,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2019,3,27]],"date-time":"2019-03-27T00:00:00Z","timestamp":1553644800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"publisher","award":["R21MH109700"],"award-info":[{"award-number":["R21MH109700"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2020,2]]},"abstract":"<jats:sec><jats:label\/><jats:p>Histamine dysregulation was implicated as a rare cause of Tourette syndrome and other tic disorders a decade ago by a landmark genetic study in a high density family pedigree, which implicated a hypomorphic mutation in the <jats:italic>histidine decarboxylase<\/jats:italic> (<jats:italic>Hdc<\/jats:italic>) gene as a rare but high penetrance genetic cause. Studies in <jats:italic>Hdc<\/jats:italic> knockout (KO) mice have confirmed that this mutation causes tic\u2010relevant behavioural and neurochemical abnormalities that parallel what is seen in patients and thus validate the KO as a potentially informative model of tic pathophysiology. Recent studies have focused on the potential role of the histamine H<jats:sub>3<\/jats:sub> receptor in this model, and by association in tic disorders and related neuropsychiatric conditions. The H<jats:sub>3<\/jats:sub> receptor is up\u2010regulated in the striatum in <jats:italic>Hdc<\/jats:italic> KO mice. As the H<jats:sub>3<\/jats:sub> receptor has constitutive activity in the absence of ligand, this receptor up\u2010regulation may have significant cellular effects despite the absence of neurotransmitter histamine in these mice. Activation in vivo of H<jats:sub>3<\/jats:sub> receptors in wild type mice regulates signalling in striatal medium spiny neurons (MSNs) that interacts non\u2010linearly with dopamine receptor signalling. Baseline signalling alterations in MSNs in <jats:italic>Hdc<\/jats:italic> KO mice resemble those seen after H<jats:sub>3<\/jats:sub> receptor agonist treatment in wild type animals. H<jats:sub>3<\/jats:sub> receptor agonist treatment in the KOs further accentuates most of these signalling abnormalities and produces behavioural stereotypy. Together, these data suggest the intriguing hypothesis that constitutive signalling by up\u2010regulated H<jats:sub>3<\/jats:sub> receptors explains many of the molecular and behavioural abnormalities seen in these animals.<\/jats:p><\/jats:sec><jats:sec><jats:title>Linked Articles<\/jats:title><jats:p>This article is part of a themed section on New Uses for 21st Century. 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