Worsening of Huntington disease phenotype in CB1 receptor knockout mice

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Abstract

Huntington's disease (HD) is a progressive neurodegenerative genetic disorder which leads to motor, cognitive and psychiatric disturbances. The primary neuropathological hallmark is atrophy of the striatum. Cannabinoid CB1 receptors (CB1Rs) are particularly enriched in the striatum and previous works indicate their early loss of expression in HD, even before symptom occurrence. However, pathophysiological significance of this loss of expression remains unclear. In addition, whether specific modulation of CB1R is able to mitigate striatal neuron fate in HD remains currently controversial. In order to gain further insights on the potential role of CB1R in HD physiopathology, we evaluated the pathophysiological consequences of a genetic deletion of CB1R in the N171-82Q transgenic model and following 3-nitropropionic (3NP) intoxication. Taken together our data demonstrate that CB1R knockout (1) worsens motor performances in N171-82Q mice and (2) increases mouse susceptibility to 3NP. These results suggest that functional changes in CB1R may contribute to the physiopathological development of HD.

Research Highlights

► Loss of CB1R expression worsens motor performance and increases striatal aggregates in HD mice. ► Loss of CB1R expression worsens motor performance and increases striatal lesions induced by 3NP intoxication. ► Results support that early loss of CB1 receptors seen in HD is involved in the pathophysiological development of this disorder.

Introduction

HD is an autosomal dominantly inherited neurodegenerative disorder characterized by involuntary abnormal movements, psychiatric disturbances and cognitive alterations (Walker, 2007). HD is caused by mutations in the IT15/HD1 gene that encodes Huntingtin protein (Walker, 2007). The mutation consists of a CAG triplet repeat expansion that is translated into an abnormally long polyglutamine (polyQ) tract (> 39) within the N-terminal region of the protein (The Huntington's Disease Collaborative Research Group, 1993). Although several cerebral regions show signs of neurodegeneration in HD, the primary neuropathological hallmark is atrophy of the striatum (Brouillet et al., 1999, Vonsattel et al., 1985). Several molecular mechanisms underlie striatal degeneration in HD (see Bantubungi and Blum, 2007a, Bantubungi and Blum, 2007b for reviews). For instance, loss of BDNF production/transport (Zuccato and Cattaneo, 2009, Roze et al., 2008), excitotoxicity and mitochondrial complex II inhibition (Brouillet et al., 1999, Brouillet et al., 2005) have been particularly viewed as instrumental in HD.

Endocannabinoid CB1 receptors (CB1Rs) are G protein-coupled receptors strongly expressed in the basal ganglia, and particularly in the striatum at both pre- and post-synaptic levels (Kofalvi et al., 2005, Mailleux and Vanderhaeghen, 1992, Uchigashima et al., 2007). In HD patients, one of the earliest neurochemical alterations observed is the loss of CB1R binding in the striatum (Glass et al., 2000). In transgenic mouse models of HD, the decrease in CB1R mRNA takes place before the onset of motor symptoms (Denovan-Wright and Robertson, 2000, Naver et al., 2003, Dowie et al., 2009). Interestingly, it has been reported in the R6/1 transgenic model of HD that environmental enrichment upregulates CB1R binding and provides behavioral improvement (Glass et al., 2004) suggesting that early loss of CB1R may be detrimental in HD and that activation of the CB1R pathway could afford protection. However, despite the fact that activation of the endocannabinoid system has been viewed as promising in HD (Fernandez-Ruiz, 2009, Maccarrone et al., 2007), the pathophysiological consequences of CB1R early loss remains unknown and whether their activation is beneficial in animal models of HD still remains unclear (Dowie et al., 2010, Lastres-Becker et al., 2003, Lastres-Becker et al., 2004, Pintor et al., 2006, Sagredo et al., 2007). In the present study, we evaluated the physiopathological consequences of an early and global lack of CB1R expression in two mouse models of HD: a transgenic model expressing a mutated Huntingtin (N171-82Q strain; Schilling et al., 1999) as well as a phenotypic model induced by 3NP injection, an irreversible inhibitor of succinate dehydrogenase (SDH; mitochondrial complex II), leading to striatal lesions reminiscent of Huntington's disease (Brouillet et al., 2005).

Section snippets

Animals

A stable colony of N171-82Q mice (B6C3F1, Schilling et al., 1999), expressing an N-terminal fragment of Huntingtin protein with 82 glutamine repeats, has been maintained at the Université Libre de Bruxelles with founders from the Jackson Laboratory (Bar Harbor, USA). Life-span of our N171-82Q colony was about 170 days in our housing conditions as we previously reported (Mievis et al., 2007, Mievis et al., 2011) and as described in other works (Duan et al., 2008, Masuda et al., 2008). Double

Survival and motor coordination in N171-82Q mice in the absence of CB1R

We first evaluated the effects induced by genetic deletion of CB1R in the N171-82Q HD strain. Survival of HD CB1−/− (115.8±3.8 days; n = 64) was found similar to HD CB1+/+ animals (125.9±3.9 days; n = 62) despite a trend towards decrease (P = 0.066, Log-Rank Mantel-Cox test; Fig. 1A). Two-way ANOVA showed no significant interaction between survival and gender ((F(1,122) = 0.21; P = 0.649). Survival of non-HD littermates (data not shown) remained unaffected by CB1 receptor gene deletion in agreement with

Discussion

Expression of CB1Rs is found decreased early in post-mortem brains from HD patients as well as in phenotypic and genetic HD models (Denovan-Wright and Robertson, 2000, Dowie et al., 2009, Glass et al., 2000, Lastres-Becker et al., 2002, Lastres-Becker et al., 2003, Naver et al., 2003). Although CB1R loss might simply be a consequence of neuronal degeneration, the decrease in CB1R expression observed before symptom occurrence (Denovan-Wright and Robertson, 2000, Naver et al., 2003, Dowie et al.,

Acknowledgments

IRIBHM is supported by the Interuniversity Attraction Poles Programme (P6-14)—Belgian State—Belgian Science Policy, the Fondation Médicale Reine Elisabeth, the Walloon Region (Programme d'Excellence “CIBLES”) and the Fonds National de la Recherche Scientifique. Inserm U837 is supported by Inserm, CNRS, IMPRT, University of Lille2, Lille County Hospital (CHRU-Lille), Région Nord-Pas-de-Calais. CL is a chercheur qualifié at the Fonds National de la Recherche Scientifique. DB is an Inserm

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    These authors equally contributed to this work.

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