Huntington disease (HD) is a genetic neurodegenerative disorder that affects about 6,000 people in France. Psychiatric manifestations are an important component of the early symptoms of the disease. Indeed, depressive episodes sometimes associated with generalized anxiety are commonly observed during the pre-symptomatic stages of disease. Few information is available about the reasons for this high prevalence.The allele responsible for the disease encodes a protein called huntingtin (HTT) whose polyglutamine expansion (polyQ) in the N-terminal region is longer than in the non-pathogenic HTT. Huntingtin is involved in various cellular functions including the transport and the expression of a neurotrophic factor, the Brain-Derived Neurotrophic Factor (BDNF). This factor is also known for its role in the regulation of mood, adult hippocampal neurogenesis, and in the therapeutic response to antidepressants.We hypothesized that huntingtin, in addition to its known roles in the cortex and striatum, may play a role in the hippocampus. Thus, an impaired transport of BDNF in the hippocampus could partly explain the mood disorders observed in HD patients.By an in vivo approach using different mouse models, we demonstrated that huntingtin stimulates vesicular trafficking and secretion of BDNF in hippocampal neurons and that this action may be modulated by the polyQ mutation or by the phosphorylation status of the protein on serines 1181 and 1201. These lead to changes in signaling pathways (Akt, ERK, CREB) activated by BDNF.We also demonstrate that normal huntingtin is involved in the support provided by mature neurons to new neurons for their long-term survival and the formation of a complex dendritic arborization. BDNF is the ideal candidate to mediate these effects on hippocampal neurogenesis. Finally, normal huntingtin and its mutated forms (polyQ and phosphorylated on serines 1181 and 1201) are involved in anxiety and depressive-like phenotype in mice.
