title: Dysregulated intracellular signaling in the striatum in a pathophysiologically grounded model of Tourette syndrome.
abstract: Tic disorders produce substantial morbidity, but their pathophysiology remains poorly understood. Convergent evidence suggests that dysregulation of the cortico-basal ganglia circuitry is central to the pathogenesis of tics. Tourette syndrome (TS), the most severe end of the continuum of tic disorders, is substantially genetic, but causative mutations have been elusive. We recently described a mouse model, the histidine decarboxylase (Hdc) knockout mouse, that recapitulates a rare, highly penetrant mutation found in a single family; these mice exhibit TS-like phenomenology. These animals have a global deficit in brain histamine and a consequent dysregulation of DA in the basal ganglia. Histamine modulation of DA effects is increasingly appreciated, but the mechanisms underlying this modulation remain unclear; the consequences of modest DA elevation in the context of profound HA deficiency are difficult to predict, but understanding them in the Hdc knockout mouse may provide generalizable insights into the pathophysiology of TS. Here we characterized signaling pathways in striatal cells in this model system, at baseline and after amphetamine challenge. In vivo microdialysis confirms elevated DA in Hdc-KO mice. We find dephosphorylation of Akt and its target GSK3β and activation of the MAPK signaling cascade and its target rpS6; these are characteristic of the effects of DA on D2- and D1-expressing striatal neurons, respectively. Strikingly, there is no alteration in mTOR signaling, which can be regulated by DA in both cell types. These cellular effects help elucidate striatal signaling abnormalities in a uniquely validated mouse model of TS and move towards the identification of new potential therapeutic targets for tic disorders.
authors.affiliation: Department of Psychiatry, Yale University, New Haven, CT, USA; Ribicoff Research Facilities, Yale University, New Haven, CT, USA.
authors.forename: Maximiliano
authors.initials: M
authors.lastname: Rapanelli
authors.affiliation: Department of Psychiatry, Yale University, New Haven, CT, USA; Ribicoff Research Facilities, Yale University, New Haven, CT, USA.
authors.forename: Luciana R
authors.initials: LR
authors.lastname: Frick
authors.affiliation: Department of Psychiatry, Yale University, New Haven, CT, USA; Ribicoff Research Facilities, Yale University, New Haven, CT, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Pogorelov
authors.affiliation: Department of Psychiatry, Yale University, New Haven, CT, USA; Ribicoff Research Facilities, Yale University, New Haven, CT, USA.
authors.forename: Kristie T
authors.initials: KT
authors.lastname: Ota
authors.affiliation: Department of Psychiatry, Yale University, New Haven, CT, USA; Ribicoff Research Facilities, Yale University, New Haven, CT, USA.
authors.forename: Eeman
authors.initials: E
authors.lastname: Abbasi
authors.affiliation: Tohoku University, Graduate School of Engineering, Sendai, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohtsu
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; Interdepartmental Neuroscience Program, Yale University, New Haven, CT, USA; Ribicoff Research Facilities, Yale University, New Haven, CT, USA. Electronic address: Christopher.pittenger@yale.edu.
authors.forename: Christopher
authors.initials: C
authors.lastname: Pittenger
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006640:Histidine Decarboxylase / Q000235:genetics*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation; D038601:Ribosomal Protein S6 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D005879:Tourette Syndrome / Q000378:metabolism*
chemical_list: D038601:Ribosomal Protein S6; C448579:ribosomal protein S6, mouse; D000661:Amphetamine; C546843:mTOR protein, mouse; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3; D006640:Histidine Decarboxylase; D004298:Dopamine
keywords: Basal ganglia; Dopamine; Histamine; Striatum; Tourette syndrome