title: The ANK3 bipolar disorder gene regulates psychiatric-related behaviors that are modulated by lithium and stress.
abstract: BACKGROUND
  Ankyrin 3 (ANK3) has been strongly implicated as a risk gene for bipolar disorder (BD) by recent genome-wide association studies of patient populations. However, the genetic variants of ANK3 contributing to BD risk and their pathological function are unknown.
  
  
  METHODS
  To gain insight into the potential disease relevance of ANK3, we examined the function of mouse Ank3 in the regulation of psychiatric-related behaviors using genetic, neurobiological, pharmacological, and gene-environment interaction (G×E) approaches. Ank3 expression was reduced in mouse brain either by viral-mediated RNA interference or through disruption of brain-specific Ank3 in a heterozygous knockout mouse.
  
  
  RESULTS
  RNA interference of Ank3 in hippocampus dentate gyrus induced a highly specific and consistent phenotype marked by decreased anxiety-related behaviors and increased activity during the light phase, which were attenuated by chronic treatment with the mood stabilizer lithium. Similar behavioral alterations of reduced anxiety and increased motivation for reward were also exhibited by Ank3+/- heterozygous mice compared with wild-type Ank3+/+ mice. Remarkably, the behavioral traits of Ank3+/- mice transitioned to depression-related features after chronic stress, a trigger of mood episodes in BD. Ank3+/- mice also exhibited elevated serum corticosterone, suggesting that reduced Ank3 expression is associated with elevated stress reactivity.
  
  
  CONCLUSIONS
  This study defines a new role for Ank3 in the regulation of psychiatric-related behaviors and stress reactivity that lends support for its involvement in BD and establishes a general framework for determining the disease relevance of genes implicated by patient genome-wide association studies.
authors.affiliation: Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research and Department of Psychiatry, Massachusetts General Hospital, USA.
authors.forename: Melanie P
authors.initials: MP
authors.lastname: Leussis
authors.forename: Erin M
authors.initials: EM
authors.lastname: Berry-Scott
authors.forename: Mai
authors.initials: M
authors.lastname: Saito
authors.forename: Hueihan
authors.initials: H
authors.lastname: Jhuang
authors.forename: Georgius
authors.initials: G
authors.lastname: de Haan
authors.forename: Ozan
authors.initials: O
authors.lastname: Alkan
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Luce
authors.forename: Jon M
authors.initials: JM
authors.lastname: Madison
authors.forename: Pamela
authors.initials: P
authors.lastname: Sklar
authors.forename: Thomas
authors.initials: T
authors.lastname: Serre
authors.forename: David E
authors.initials: DE
authors.lastname: Root
authors.forename: Tracey L
authors.initials: TL
authors.lastname: Petryshen
mesh_terms: D000818:Animals; D017487:Ankyrins / Q000235:genetics* / Q000502:physiology; D001008:Anxiety Disorders / Q000097:blood / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology*; D001714:Bipolar Disorder / Q000235:genetics*; D003345:Corticosterone / Q000097:blood; D018891:Dentate Gyrus / Q000502:physiology; D018021:Lithium Chloride / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D013315:Stress, Psychological / Q000097:blood / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology*
chemical_list: C094681:Ank3 protein, mouse; D017487:Ankyrins; D018021:Lithium Chloride; D003345:Corticosterone