Huntingtin mediates anxiety/depression-related behaviors and hippocampal neurogenesis

J Neurosci. 2013 May 15;33(20):8608-20. doi: 10.1523/JNEUROSCI.5110-12.2013.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Anxiety / genetics
  • Anxiety / pathology*
  • Anxiety / physiopathology
  • Brain-Derived Neurotrophic Factor / metabolism
  • Bromodeoxyuridine / metabolism
  • Depression / pathology*
  • Depression / physiopathology
  • Disease Models, Animal
  • Doublecortin Domain Proteins
  • Hippocampus / physiopathology*
  • Huntingtin Protein
  • Immunoprecipitation
  • In Situ Nick-End Labeling
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microtubule-Associated Proteins / metabolism
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neurogenesis / genetics*
  • Neurogenesis / physiology
  • Neuropeptides / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Phosphorylation / genetics
  • Protein Transport / genetics
  • Serine / genetics
  • Serine / metabolism

Substances

  • Brain-Derived Neurotrophic Factor
  • Doublecortin Domain Proteins
  • Htt protein, mouse
  • Huntingtin Protein
  • Microtubule-Associated Proteins
  • Nerve Tissue Proteins
  • Neuropeptides
  • Nuclear Proteins
  • Serine
  • Bromodeoxyuridine