title: Autism gene variant causes hyperserotonemia, serotonin receptor hypersensitivity, social impairment and repetitive behavior.
abstract: Fifty years ago, increased whole-blood serotonin levels, or hyperserotonemia, first linked disrupted 5-HT homeostasis to Autism Spectrum Disorders (ASDs). The 5-HT transporter (SERT) gene (SLC6A4) has been associated with whole blood 5-HT levels and ASD susceptibility. Previously, we identified multiple gain-of-function SERT coding variants in children with ASD. Here we establish that transgenic mice expressing the most common of these variants, SERT Ala56, exhibit elevated, p38 MAPK-dependent transporter phosphorylation, enhanced 5-HT clearance rates and hyperserotonemia. These effects are accompanied by altered basal firing of raphe 5-HT neurons, as well as 5HT(1A) and 5HT(2A) receptor hypersensitivity. Strikingly, SERT Ala56 mice display alterations in social function, communication, and repetitive behavior. Our efforts provide strong support for the hypothesis that altered 5-HT homeostasis can impact risk for ASD traits and provide a model with construct and face validity that can support further analysis of ASD mechanisms and potentially novel treatments.
authors.affiliation: Department of Psychiatry, Vanderbilt University, Nashville, TN 37232, USA. j.vvw@vanderbilt.edu
authors.forename: Jeremy
authors.initials: J
authors.lastname: Veenstra-VanderWeele
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Muller
authors.forename: Hideki
authors.initials: H
authors.lastname: Iwamoto
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Sauer
authors.forename: W Anthony
authors.initials: WA
authors.lastname: Owens
authors.forename: Charisma R
authors.initials: CR
authors.lastname: Shah
authors.forename: Jordan
authors.initials: J
authors.lastname: Cohen
authors.forename: Padmanabhan
authors.initials: P
authors.lastname: Mannangatti
authors.forename: Tammy
authors.initials: T
authors.lastname: Jessen
authors.forename: Brent J
authors.initials: BJ
authors.lastname: Thompson
authors.forename: Ran
authors.initials: R
authors.lastname: Ye
authors.forename: Travis M
authors.initials: TM
authors.lastname: Kerr
authors.forename: Ana M
authors.initials: AM
authors.lastname: Carneiro
authors.forename: Jacqueline N
authors.initials: JN
authors.lastname: Crawley
authors.forename: Elaine
authors.initials: E
authors.lastname: Sanders-Bush
authors.forename: Douglas G
authors.initials: DG
authors.lastname: McMahon
authors.forename: Sammanda
authors.initials: S
authors.lastname: Ramamoorthy
authors.forename: Lynette C
authors.initials: LC
authors.lastname: Daws
authors.forename: James S
authors.initials: JS
authors.lastname: Sutcliffe
authors.forename: Randy D
authors.initials: RD
authors.lastname: Blakely
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000097:blood / Q000235:genetics* / Q000503:physiopathology; D004195:Disease Models, Animal; D006706:Homeostasis; D051379:Mice; D011985:Receptors, Serotonin / Q000502:physiology*; D012701:Serotonin / Q000097:blood*; D012919:Social Behavior; D013239:Stereotyped Behavior
chemical_list: D011985:Receptors, Serotonin; D012701:Serotonin