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.
Highlights
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by expansion of CAG repeats in exon 1 of the huntingtin gene
Altered affective behaviors in female HD mice Measuring the time of immobility in the forced-swimming test (FST), we found overall effects of genotype (F(1,97) = 11.7, p,0.001) and treatment (F(1,97) = 10.3, p,0.01) as well as a significant interaction between sex and genotype (F(1,97) = 6.36, p,0.01)
Despite evidence of affective disorders in HD and the known susceptibility of female to developing depression in the general population, there has yet to be a study of sexual dimorphism in the development and presentation of depression in HD patients
Summary
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by expansion of CAG repeats in exon 1 of the huntingtin gene. Clinical onset of HD is determined on the basis of motor symptoms, the pre-motor stages of the disease are commonly associated with depression [1,2,3,4]. While HD is an autosomal dominant condition that affects both males and females, there is yet to be a study of sexual dimorphism in the development and presentation of depression in HD patients. Clinical studies suggest gender differences in the associations observed between psychiatric disorders and functional polymorphisms of 5-HT transporter (5HTT) [8,9,10,11] and tryptophan hydroxylase-2 (TPH2) [12,13]
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