Huntingtin mediates anxiety/depression-related behaviors and hippocampal neurogenesis

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...

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Bibliographic Details
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
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Summary: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.
ISSN:0270-6474
1529-2401
1529-2401
DOI:10.1523/JNEUROSCI.5110-12.2013