Sexually Dimorphic Serotonergic Dysfunction in a Mouse Model of Huntington’s Disease and Depression Thibault Renoir1*, Michelle S. Zajac1,2, Xin Du1,2, Terence Y. Pang1, Leah Leang 1 , Caroline Chevarin3,4, Laurence Lanfumey3,4, Anthony J. Hannan1,2 1 Howard Florey Institute, Florey Neuroscience Institutes, University of Melbourne, Parkville, Australia, 2 Department of Anatomy and Cell Biology, University of Melbourne, Parkville, Australia, 3 Inserm UMR S894, Paris, France, 4 UPMC, Univ Paris 06, UMR S894, Paris, France 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. Citation: Renoir T, Zajac MS, Du X, Pang TY, Leang L, et al. (2011) Sexually Dimorphic Serotonergic Dysfunction in a Mouse Model of Huntington’s Disease and Depression. PLoS ONE 6(7): e22133. doi:10.1371/journal.pone.0022133 Editor: Kenji Hashimoto, Chiba University Center for Forensic Mental Health, Japan Received April 27, 2011; Accepted June 15, 2011; Published July 8, 2011 Copyright: 2011 Renoir et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by National Health and Medical Research Council (NHMRC) Project Grants (AJH), philanthropic support from a Pfizer Australia Research Fellowship (AJH), NHMRC-INSERM Exchange Fellowship (TR) and University of Melbourne Research Scholarships (MSZ and XD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: thibault.renoir@florey.edu.au Introduction Huntington’s disease (HD) is an autosomal dominant neurode- generative 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, however the pre-motor stages of the disease are commonly associated with depression [1,2,3,4] Mood disorders are one of the most prevalent causes of disability worldwide and depression is diagnosed in women at roughly twice the incidence of men in the general population [5,6]. 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. However our recent findings in a HD mouse model suggest such clinical investigation is warranted. One hypothesis addressing the sexual dimorphism of depression involves the monoamine neurotransmitter serotonin (5-HT) [7]. Clinical studies suggest gender differences in the associations observed between psychiatric disorders and functional polymorphisms of 5-HT transporter (5- HTT) [8,9,10,11] and tryptophan hydroxylase-2 (TPH2) [12,13]. The 5-HT1A and 5-HT2 receptors are also of particular interest with respect to both pathogenesis and antidepressant efficacy [14]. Major depression has been associated with increased 5-HT1A autoreceptor density in the dorsal raphe nucleus and/or reduced postsynaptic 5-HT1A/5-HT2 receptor function [15,16,17,18,19], sometimes in a gender-specific manner [20]. Furthermore, the desensitization of the 5-HT1A autoreceptor has been demonstrated to be essential for enhanced 5-HT transmission following chronic treatment with selective 5-HT reuptake inhibitors [21]. Finally, 5- HT1A and/or 5-HT2 receptor abnormalities have been described in different rodent models of mood disorders [22,23,24,25] and HD [26,27,28]. The neurobiological basis for the increased incidence of depression in HD remains unclear. Therefore, establishment and validation of an animal model of HD with depression-like behaviors will provide a valuable tool for understanding the mechanisms of the condition as well as the preclinical development of effective therapies. A depressive-like phenotype has recently been observed in two different mouse models of HD [27,29]. However, these studies did not satisfactorily rule out potential confounds associated with the locomotor/cognitive impairments and did not functionally assess the possible mechanism(s) underlying the depressive-like behaviors. Using the R6/1 transgenic HD mice which express exon 1 of the mutant human huntingtin gene, we recently revealed sex-specific changes in relation to the effects of HD mutation [27,30]. On the PLoS ONE | www.plosone.org 1 July 2011 | Volume 6 | Issue 7 | e22133