Sexually Dimorphic Serotonergic Dysfunction in a Mouse Model of Huntington's Disease and Depression

Abstract

Depression is the most common psychiatric disorder in Huntington's disease (HD) patients. In the general population, women are more prone to develop depression and such susceptibility might be related to serotonergic dysregulation. There is yet to be a study of sexual dimorphism in the development and presentation of depression in HD patients. We investigated whether 8-week-old male and female R6/1 transgenic HD mice display depressive-like endophenotypes associated with serotonergic impairments. We also studied the behavioral effects of acute treatment with sertraline. We found that only female HD mice exhibited a decreased preference for saccharin as well as impaired emotionality-related behaviors when assessed on the novelty-suppressed feeding test (NSFT) and the forced-swimming test (FST). The exaggerated immobility time displayed by female HD in the FST was reduced by acute administration of sertraline. We also report an increased response to the 5-HT1A receptor agonist 8-OH-DPAT in inducing hypothermia and a decreased 5-HT2A receptor function in HD animals. While tissue levels of serotonin were reduced in both male and female HD mice, we found that serotonin concentration and hydroxylase-2 (TPH2) mRNA levels were higher in the hippocampus of males compared to female animals. Finally, the antidepressant-like effects of sertraline in the FST were blunted in male HD animals. This study reveals sex-specific depressive-related behaviors during an early stage of HD prior to any cognitive and motor deficits. Our data suggest a crucial role for disrupted serotonin signaling in mediating the sexually dimorphic depression-like phenotype in HD mice.

Short-term memory acquisition in female Huntington's disease mice is vulnerable to acute stress

“…Overall, our results suggest that, compared to WT animals, HD mice are more vulnerable to the negative effect of stress on short-term memory only when confinement stress is administered prior to the training trial. This observation is consistent with the female HD-specific depressive-like behavioural phenotype elicited by exposure to acute stressors such as forced-swim and novelty-suppressed feeding [19,20]. Female HD mice thus appear hyper-responsive to the detrimental effects of acute stress, in both affective-related responses and in memory acquisition.…”

“…Previous studies by our group found HD female-specific abnormalities in stress-related behaviours [19,20]. In the present study, male HD mice showed no preference for the novel arm in the nonstress condition ( Fig.…”

“…as mild as possible so as not to impair wild-type animals) was the most suitable for this study. Also, since swimming performance has been shown to be altered in 8-weekold female HD mice [20], the use of swim stress would have been a potential confound. Our present female HD-specific deficit was not due to stress effects on exploration in the Y-maze ( Fig.…”

Metaplastic Regulation of the Median Raphe Nucleus via Serotonin 5-HT1A Receptor on Hippocampal Synaptic Plasticity Is Associated With Gender-Specific Emotional Expression in Rats

“…More recently, Renoir et al (70) demonstrated that the hippocampal 5-HT levels were lower in female mice compared with male mice. Hypothermia responses to 8-OH DPAT, as a measure of 5-HT 1A receptor function, were smaller in the female mice.…”

Disease stage, but not sex, predicts depression and psychological distress in Huntington's disease: A European population study

“…The forced swimming test is another measure that may represent depressive-like behaviour through reduced swimming and climbing activity. In these tests, female mice have been shown to demonstrate more behaviours suggestive of depression [22][23][24]. Therefore, collectively, there is evidence of sexual dimorphism of anxiety and depressive-like behaviours in rodent models of HD, with suggestion of a potential interaction between sex differences and stage of disease progression [19], an area that has not been examined in humans.…”