Mood disorders in Huntington's disease: from behavior to cellular and molecular mechanisms

Abstract

Huntington's disease (HD) is a neurodegenerative disorder that is best known for its effect on motor control. Mood disturbances such as depression, anxiety, and irritability also have a high prevalence in patients with HD, and often start before the onset of motor symptoms. Various rodent models of HD recapitulate the anxiety/depressive behavior seen in patients. HD is caused by an expanded polyglutamine stretch in the N-terminal part of a 350 kDa protein called huntingtin (HTT). HTT is ubiquitously expressed and is implicated in several cellular functions including control of transcription, vesicular trafficking, ciliogenesis, and mitosis. This review summarizes progress in efforts to understand the cellular and molecular mechanisms underlying behavioral disorders in patients with HD. Dysfunctional HTT affects cellular pathways that are involved in mood disorders or in the response to antidepressants, including BDNF/TrkB and serotonergic signaling. Moreover, HTT affects adult hippocampal neurogenesis, a physiological phenomenon that is implicated in some of the behavioral effects of antidepressants and is linked to the control of anxiety. These findings are consistent with the emerging role of wild-type HTT as a crucial component of neuronal development and physiology. Thus, the pathogenic polyQ expansion in HTT could lead to mood disorders not only by the gain of a new toxic function but also by the perturbation of its normal function.

Keywords: BDNF; HPA axis; Huntingtin; Huntington's disease; anxiety; depression; neurogenesis; serotonin.

Figure 1

HTT affects BDNF/TrkB signaling at many levels. HTT regulates BDNF transcription (via the sequestration of REST/NRSF), BDNF vesicular trafficking (via interaction with the molecular motors dynein and kinesin), the activity-dependent release of BDNF, and also TrkB retrograde vesicular trafficking (via HAP1 interaction). HTT also affects Rab11-dependent endosomal recycling. HTT could also modulate TrkB endocytosis via its interaction with HAP40 and early endosomal trafficking via its interaction with Rab5. See references in the text.

Figure 2

Many defects at various locations in the brain of HD murine models can be linked to mood disorders. Studies in mouse models of HD have shown that BDNF/TrkB signaling is altered in various brain regions. Alterations of the serotonergic system and of the HPA axis have also been documented. AG, adrenal gland; Amy, amygdala; Ctx, cortex; Hip, hippocampus; Hyp, hypothalamus; Ra, raphe nuclei. See references in the text.