title: Histamine H3R receptor activation in the dorsal striatum triggers stereotypies in a mouse model of tic disorders.
abstract: Tic disorders affect ~5% of the population and are frequently comorbid with obsessive-compulsive disorder, autism, and attention deficit disorder. Histamine dysregulation has been identified as a rare genetic cause of tic disorders; mice with a knockout of the histidine decarboxylase (Hdc) gene represent a promising pathophysiologically grounded model. How alterations in the histamine system lead to tics and other neuropsychiatric pathology, however, remains unclear. We found elevated expression of the histamine H3 receptor in the striatum of Hdc knockout mice. The H3 receptor has significant basal activity even in the absence of ligand and thus may modulate striatal function in this knockout model. We probed H3R function using specific agonists. The H3 agonists R-aminomethylhistamine (RAMH) and immepip produced behavioral stereotypies in KO mice, but not in controls. H3 agonist treatment elevated intra-striatal dopamine in KO mice, but not in controls. This was associated with elevations in phosphorylation of rpS6, a sensitive marker of neural activity, in the dorsal striatum. We used a novel chemogenetic strategy to demonstrate that this dorsal striatal activity is necessary and sufficient for the development of stereotypy: when RAMH-activated cells in the dorsal striatum were chemogenetically activated (in the absence of RAMH), stereotypy was recapitulated in KO animals, and when they were silenced the ability of RAMH to produce stereotypy was blocked. These results identify the H3 receptor in the dorsal striatum as a contributor to repetitive behavioral pathology.
authors.affiliation: Department of Psychiatry, Yale University, New Haven, CT, USA.
authors.forename: M
authors.initials: M
authors.lastname: Rapanelli
authors.affiliation: Department of Psychiatry, Yale University, New Haven, CT, USA.
authors.forename: L
authors.initials: L
authors.lastname: Frick
authors.affiliation: Department of Psychiatry, Yale University, New Haven, CT, USA.
authors.forename: V
authors.initials: V
authors.lastname: Pogorelov
authors.affiliation: Graduate School of Engineering, Tohoku University, Sendai, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Ohtsu
authors.affiliation: Department of Neurochemistry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Bito
authors.affiliation: Department of Psychiatry, Yale University, New Haven, CT, USA.|Department of Psychology, Yale University, New Haven, CT, USA.|Child Study Center, Yale University, New Haven, CT, USA.|Interdepartental Neuroscience Program, Yale University, New Haven, CT, USA.
authors.forename: C
authors.initials: C
authors.lastname: Pittenger
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D017442:Histamine Agonists / Q000494:pharmacology*; D006640:Histidine Decarboxylase / Q000235:genetics; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D038601:Ribosomal Protein S6 / Q000187:drug effects / Q000378:metabolism; D013239:Stereotyped Behavior / Q000187:drug effects*; D013981:Tic Disorders / Q000235:genetics* / Q000378:metabolism
chemical_list: D017442:Histamine Agonists; D007093:Imidazoles; D010880:Piperidines; D018100:Receptors, Histamine H3; D038601:Ribosomal Protein S6; C448579:ribosomal protein S6, mouse; C085755:4-(1H-imidazol-4-ylmethyl)piperidine; D006640:Histidine Decarboxylase; D004298:Dopamine