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Pathogenic mechanisms
B14 Huntingtin mediates anxiety/depression-related behaviours in mouse through BDNF transport and hippocampal neurogenesis
  1. K Ben M'Barek1,
  2. S Orvoen2,
  3. P Pla1,
  4. C Benstaali1,
  5. J Godin1,
  6. A Gardier2,
  7. F Saudou1,
  8. D David2,
  9. S Humbert1
  1. 1Institut Curie, Cnrs Umr 3306—Inserm U1005, Orsay, France
  2. 2University of Paris-Sud, EA3544, Faculté de Pharmacie, Châtenay-Malabry, France

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 behaviours through its phosphorylation at serines 1181 and 1201, two cyclin-dependent kinase 5 phosphorylation sites. Indeed, genetic phospho-ablation at serines 1181 and 1201 in mouse reduces basal levels of anxiety/depression-like behaviours in mouse. These behavioural effects directly depend on increased adult hippocampal neurogenesis. Indeed, focal dentate gyrus irradiation impaired neurogenesis but also anxiety/depression-related behaviour. Finally, the state of phosphorylation of huntingtin regulates neurogenesis as it influences brain-derived neurotrophic factor transport and subsequent signalling.

DD and SH are both equal last authors.

  • Neurogenesis
  • BDNF transport
  • anxiety/depression
  • hippocampus

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