Mood Disorders in Huntington's Disease
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REVIEW ARTICLE published: 23 April 2014 BEHAVIORAL NEUROSCIENCE doi: 10.3389/fnbeh.2014.00135 Mood disorders in Huntington’s disease: from behavior to cellular and molecular mechanisms Patrick Pla 1,2,3,4, Sophie Orvoen 5, Frédéric Saudou 1,2,3, Denis J. David 5 and Sandrine Humbert 1,2,3* 1 Institut Curie, Orsay, France 2 CNRS UMR3306, Orsay, France 3 INSERM U1005, Orsay, France 4 Faculté des Sciences, Université Paris-Sud, Orsay, France 5 EA3544, Faculté de Pharmacie, Université Paris-Sud, Châtenay-Malabry, France Edited by: Huntington’s disease (HD) is a neurodegenerative disorder that is best known for its Benjamin Adam Samuels, Columbia effect on motor control. Mood disturbances such as depression, anxiety, and irritability University, USA also have a high prevalence in patients with HD, and often start before the onset Reviewed by: of motor symptoms. Various rodent models of HD recapitulate the anxiety/depressive Catherine Belzung, Université Francois Rabelais, France behavior seen in patients. HD is caused by an expanded polyglutamine stretch in Emmanuel Brouillet, Commissariat à the N-terminal part of a 350 kDa protein called huntingtin (HTT). HTT is ubiquitously l’Energie Atomique and Centre expressed and is implicated in several cellular functions including control of transcription, National de la Recherche vesicular trafficking, ciliogenesis, and mitosis. This review summarizes progress in Scientifique, France efforts to understand the cellular and molecular mechanisms underlying behavioral *Correspondence: Sandrine Humbert, Institut Curie, disorders in patients with HD. Dysfunctional HTT affects cellular pathways that are Bâtiment 110, 91405 Orsay Cedex, involved in mood disorders or in the response to antidepressants, including BDNF/TrkB France and serotonergic signaling. Moreover, HTT affects adult hippocampal neurogenesis, e-mail: [email protected] 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: Huntington’s disease, depression, anxiety, neurogenesis, Huntingtin, BDNF, serotonin, HPA axis INTRODUCTION HTT into smaller N-terminal fragments that contain the polyQ Huntington’s disease (HD) is a fatal neurodegenerative disor- stretch that have been shown to be highly toxic in HD cellular and der characterized by cognitive and psychiatric disturbances that mouse models (Gafni et al., 2004; Graham et al., 2006). However, are associated with loss of motor control, including chorea, dys- there is strong evidence that loss of the normal functions of tonia, and a lack of gestural coordination (Novak and Tabrizi, wild-type HTT also plays a role in pathological mechanisms 2011). These symptoms generally start to appear in midlife. A of HD. broad range of cognitive disturbances appear during HD progres- sion. Early cognitive defects are characterized by poor adaptation MOOD DISORDERS IN PATIENTS WITH HD and planification associated with deficits in executive function- Mood disturbances are prevalent not only among patients with ing and perseveration. Other defects are most prevalent during diagnosed HD but also in pre-symptomatic carriers of the HD the late stages of the disease, like learning difficulties and working gene (Duff et al., 2007; Julien et al., 2007; Rosenblatt, 2007) and long term memory deficits, leading to dementia (Rosenblatt, (Table 1). These disturbances include impulsivity, irritability 2007; Paulsen, 2011). (which can be accompanied by aggressiveness), anxiety, and HD is caused by an abnormal expansion of glutamine (polyQ) depression. Major depression is the most common symptom in the N-terminal part of the 350 kDa protein huntingtin (HTT). among pre-symptomatic HD carriers, although some patients This stretch is encoded by a trinucleotide CAG repetition in exon will have only part of the symptoms of the major depression, or 1ofHTT. An expansion greater than 36 repeats results in HD limited in intensity or time (Epping and Paulsen, 2011; Reedeker (Huntington Collaborative Research Group, 1993). The num- et al., 2012). Maniac depressive disorder is not particularly preva- ber of repeats is inversely correlated with the age of onset of lent in HD (Van Duijn et al., 2008; Epping and Paulsen, 2011). motor symptoms and disease onset during childhood or ado- Mood disturbances may precede the onset of the motor pheno- lescence is associated with more than 60 CAG repeats (Walker, type by 4–10 years, making them one of the earliest symptoms of 2007). HD is inherited in an autosomal dominant manner. HD. The severity of depression in HD is not dependent on disease Genetic and molecular studies have suggested that mutated progression (Berrios et al., 2001; Craufurd et al., 2001; Kingma polyQ-HTT leads to neuronal damage by gain of toxic function. et al., 2008). This suggests that different mechanisms affect neu- The pathogenic mechanism requires the cleavage of full-length rons involved in mood regulation and neurons involved in motor Frontiers in Behavioral Neuroscience www.frontiersin.org April 2014 | Volume 8 | Article 135 | 1 Pla et al. Mood disorders in Huntington’s disease and cognitive skills that are disabled in late phases of the dis- MOUSE MODELS OF HD ease in HD patients. However, mood, and cognitive alterations Various rodent models have been used to study the effect of polyQ may also share some pathogenic mechanisms as some aspects expansion in HTT (Heng et al., 2008; Pouladi et al., 2013). These of these alterations are found associated in the general popula- models differ in the number of CAG repeats, the size of the tion and in HD patients. In particular, depression and memory expressed HTT fragment, and the gene promoter used. Thus, the impairments are observed together and this is also the case for amount of mutant HTT that is expressed varies between differ- cognitive flexibility and planification defects (Smith et al., 2012; ent models. The genetic background of the mouse strains used Trivedi and Greer, 2014). Although apathy is part of symptoms to design models of HD is also important, especially because of major depression, frequency, and intensity of apathy in HD various strains perform differently in behavioral tests (Miller patients increase with disease progression contrary to depression et al., 2010; Mozhui et al., 2010). These models can be grouped (Kingma et al., 2008; Van Duijn et al., 2010). Thus, as previously according to their mode of expression of mutant HTT: transgenic suggested (Levy et al., 1998), apathy appears not only as a symp- models expressing truncated HTT, transgenic models expressing tom of depression but as a syndrome with its own dynamics and full-length HTT, and knock-in (KI) models. mechanisms. The short lifespan of mouse models prevents them from devel- The reasons underlying the frequent co-morbidity of HD and oping the same neuropathological symptoms that develop during mood disorder are still unclear. Family history of HD, especially decades in human. Large numbers of glutamines in the polyQ giventhatHDshowsadominantmodeofinheritance,isproba- stretch in the homozygous state in KI models and/or a high abun- bly an important factor. Indeed, an individual’s knowledge that dance of transgenic mutant proteins are necessary to obtain a he or she is a carrier and will inevitably experience neurologi- robust phenotype. The length of the N-terminal fragments and cal symptoms, could contribute to the prevalence of psychiatric their toxicity are inversely correlated, which underlies the robust disturbances. However, this explanation alone is not sufficient to phenotype of models in which a short N-terminal polyQ-HTT explain the high prevalence of psychiatric disturbances in HD fragment is expressed (Hackam et al., 1998; Landles et al., 2010). (Almqvist et al., 2003; Julien et al., 2007; Van Duijn et al., 2008). The sequence coding the 350 kDa HTT protein contains 67 Therefore, there are probably one or several molecular mecha- exons spanning over 170 kb of the mouse genome. Hence, the cre- nisms, independent of the psychosocial environment, that can ation of transgenic models in which full-length HTT is expressed explain the prevalence of mood disorders in patients or car- is a difficult task. Therefore in some models, the exogenous riers of HD. This hypothesis can be tested in animal models protein is limited to the N-terminal part containing the polyQ of HD. expansion, with the assumption that this portion is sufficient to There is no treatment that can halt or even slow down the pro- recapitulate some aspects of the disease. R6/1 and R6/2 mice carry gression of Huntington’s disease. Current effective treatments aim a transgene encompassing exon 1 of Htt (Mangiarini et al., 1996). to ease the symptoms of this disease. The evidence base for drugs In R6/1 mice this exon contains a polyQ tract of approximately in HD is very small so the choice of pharmacological agents is 115 residues whereas in R6/2 mice this number is 150. The pro- based mainly on clinical experience. Various molecules are used gression of HD in R6/2 and R6/1 mice is particularly fast and to treat motor dysfunction. These include neuroleptics for chorea, aggressive, therefore these mice may only be suitable