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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Analysis of Variance
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Animals
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Anxiety / genetics
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Anxiety / pathology*
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Anxiety / physiopathology
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Brain-Derived Neurotrophic Factor / metabolism
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Bromodeoxyuridine / metabolism
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Depression / pathology*
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Depression / physiopathology
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Disease Models, Animal
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Doublecortin Domain Proteins
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Hippocampus / physiopathology*
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Huntingtin Protein
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Immunoprecipitation
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In Situ Nick-End Labeling
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Microtubule-Associated Proteins / metabolism
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism*
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Neurogenesis / genetics*
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Neurogenesis / physiology
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Neuropeptides / metabolism
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Phosphorylation / genetics
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Protein Transport / genetics
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Serine / genetics
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Serine / metabolism
Substances
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Brain-Derived Neurotrophic Factor
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Doublecortin Domain Proteins
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Htt protein, mouse
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Huntingtin Protein
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Microtubule-Associated Proteins
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Nerve Tissue Proteins
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Neuropeptides
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Nuclear Proteins
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Serine
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Bromodeoxyuridine