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The histidine decarboxylase model of tic pathophysiology: a new focus on the histamine H 3 receptor
Author(s) -
Pittenger Christopher
Publication year - 2020
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.14606
Subject(s) - neurochemical , biology , receptor , histidine decarboxylase , agonist , histamine receptor , medicine , endocrinology , histamine , neuroscience , pharmacology , genetics , antagonist , histidine , amino acid
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 histidine decarboxylase (Hdc) gene as a rare but high penetrance genetic cause. Studies in Hdc knockout (KO) mice have confirmed that this mutation causes tic-relevant 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 3 receptor in this model, and by association in tic disorders and related neuropsychiatric conditions. The H 3 receptor is up-regulated in the striatum in Hdc KO mice. As the H 3 receptor has constitutive activity in the absence of ligand, this receptor up-regulation may have significant cellular effects despite the absence of neurotransmitter histamine in these mice. Activation in vivo of H 3 receptors in wild type mice regulates signalling in striatal medium spiny neurons (MSNs) that interacts non-linearly with dopamine receptor signalling. Baseline signalling alterations in MSNs in Hdc KO mice resemble those seen after H 3 receptor agonist treatment in wild type animals. H 3 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-regulated H 3 receptors explains many of the molecular and behavioural abnormalities seen in these animals. LINKED ARTICLES: This article is part of a themed section on New Uses for 21st Century. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.3/issuetoc.