title: 5-HT6receptor blockade regulates primary cilia morphology in striatal neurons.
abstract: The 5-HT6receptor has been implicated in a variety of cognitive processes including habitual behaviors, learning, and memory. It is found almost exclusively in the brain, is expressed abundantly in striatum, and localizes to neuronal primary cilia. Primary cilia are antenna-like, sensory organelles found on most neurons that receive both chemical and mechanical signals from other cells and the surrounding environment; however, the effect of 5-HT6receptor function on cellular morphology has not been examined. We confirmed that 5-HT6receptors were localized to primary cilia in wild-type (WT) but not 5-HT6knockout (5-HT6KO) in both native mouse brain tissue and primary cultured striatal neurons then used primary neurons cultured from WT or 5-HT6KO mice to study the function of these receptors. Selective 5-HT6antagonists reduced cilia length in neurons cultured from wild-type mice in a concentration and time-dependent manner without altering dendrites, but had no effect on cilia length in 5-HT6KO cultured neurons. Varying the expression levels of heterologously expressed 5-HT6receptors affected the fidelity of ciliary localization in both WT and 5-HT6KO neurons; overexpression lead to increasing amounts of 5-HT6localization outside of the cilia but did not alter cilia morphology. Introducing discrete mutations into the third cytoplasmic loop of the 5-HT6receptor greatly reduced, but did not entirely eliminate, trafficking of the 5-HT6receptor to primary cilia. These data suggest that blocking 5-HT6receptor activity reduces the length of primary cilia and that mechanisms that regulate trafficking of 5-HT6receptors to cilia are more complex than previously thought.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98104, USA; Department of Pharmacology, University of Washington, Seattle, WA 98104, USA; Graduate Program in Neuroscience, University of Washington, Seattle, WA 98104, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Brodsky
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98104, USA; Department of Pharmacology, University of Washington, Seattle, WA 98104, USA.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Lesiak
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98104, USA; Department of Pharmacology, University of Washington, Seattle, WA 98104, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Croicu
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98104, USA; Department of Pharmacology, University of Washington, Seattle, WA 98104, USA.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Cohenca
authors.affiliation: Department of Physiology & Biophysics, University of Washington, Seattle, WA 98104, USA; Graduate Program in Neuroscience, University of Washington, Seattle, WA 98104, USA.
authors.forename: Jane M
authors.initials: JM
authors.lastname: Sullivan
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98104, USA; Department of Pharmacology, University of Washington, Seattle, WA 98104, USA. Electronic address: neumaier@uw.edu.
authors.forename: John F
authors.initials: JF
authors.lastname: Neumaier
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002923:Cilia / Q000187:drug effects / Q000378:metabolism*; D003342:Corpus Striatum / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D008744:Methylamines / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011985:Receptors, Serotonin / Q000235:genetics / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors
chemical_list: D008744:Methylamines; C558330:N-(2-(3-(3-fluorophenylsulfonyl)-1H-pyrrolo(2,3-b)pyridin-1-yl)ethyl)-N,N-dimethylamine; D010879:Piperazines; D011725:Pyridines; D011985:Receptors, Serotonin; C503990:SB 399885; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013449:Sulfonamides; C097216:serotonin 6 receptor
keywords: 5-HT(6) receptors; Primary cilia; Primary cultured neurons; Serotonin; Serotonin-6; Striatum