title: Huntingtin mediates anxiety/depression-related behaviors and hippocampal neurogenesis.
abstract: Huntington disease (HD) is associated with early psychiatric symptoms including anxiety and depression. Here, we demonstrate that wild-type huntingtin, the protein mutated in HD, modulates anxiety/depression-related behaviors according to its phosphorylation at serines 1181 and 1201. Genetic phospho-ablation at serines 1181 and 1201 in mouse reduces basal levels of anxiety/depression-like behaviors. We observe that the reduction in anxiety/depression-like phenotypes is associated with increased adult hippocampal neurogenesis. By improving the attachment of molecular motors to microtubules, huntingtin dephosphorylation increases axonal transport of BDNF, a crucial factor for hippocampal adult neurogenesis. Consequently, the huntingtin-mediated increased BDNF dynamics lead to an increased delivery and signaling of hippocampal BDNF. These results support the notion that huntingtin participates in anxiety and depression-like behavior and is thus relevant to the etiology of mood disorders and anxiety/depression in HD.
authors.affiliation: Institut Curie, CNRS UMR 3306, INSERM U1005, Orsay 91405, France.
authors.forename: Karim
authors.initials: K
authors.lastname: Ben M'Barek
authors.forename: Patrick
authors.initials: P
authors.lastname: Pla
authors.forename: Sophie
authors.initials: S
authors.lastname: Orvoen
authors.forename: Caroline
authors.initials: C
authors.lastname: Benstaali
authors.forename: Juliette D
authors.initials: JD
authors.lastname: Godin
authors.forename: Alain M
authors.initials: AM
authors.lastname: Gardier
authors.forename: Frédéric
authors.initials: F
authors.lastname: Saudou
authors.forename: Denis J
authors.initials: DJ
authors.lastname: David
authors.forename: Sandrine
authors.initials: S
authors.lastname: Humbert
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D001973:Bromodeoxyuridine / Q000378:metabolism; D003863:Depression / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D006624:Hippocampus / Q000503:physiopathology*; D000071058:Huntingtin Protein; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D055495:Neurogenesis / Q000235:genetics* / Q000502:physiology; D009479:Neuropeptides / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics; D021381:Protein Transport / Q000235:genetics; D012694:Serine / Q000235:genetics / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D000089622:Doublecortin Domain Proteins; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D009687:Nuclear Proteins; D012694:Serine; D001973:Bromodeoxyuridine