Huntingtin mediates anxiety/depression-related behaviors and hippocampal neurogenesis

• Published in: The Journal of neuroscience 2013-05, Vol.33 (20), p.8608-8620
• Main Authors: Ben M'Barek, Karim, Pla, Patrick, Orvoen, Sophie, Benstaali, Caroline, Godin, Juliette D, Gardier, Alain M, Saudou, Frédéric, David, Denis J, Humbert, Sandrine
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Animals; Anxiety - genetics; Anxiety - pathology; Anxiety - physiopathology; Brain-Derived Neurotrophic Factor - metabolism; Bromodeoxyuridine - metabolism; Depression - pathology; Depression - physiopathology; Disease Models, Animal; Hippocampus - physiopathology; Immunoprecipitation; In Situ Nick-End Labeling; Life Sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microtubule-Associated Proteins - metabolism; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurobiology; Neurogenesis - genetics; Neurogenesis - physiology; Neurons and Cognition; Neuropeptides - metabolism; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Phosphorylation - genetics; Protein Transport - genetics; Sciences du vivant; Serine - genetics; Serine - metabolism
• ISSN: 0270-6474; 1529-2401; 1529-2401
• DOI: 10.1523/JNEUROSCI.5110-12.2013

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.