Worsening of Huntington disease phenotype in CB1 receptor knockout mice
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
References (44)
- et al.
Minocycline in phenotypic models of Huntington's disease
Neurobiol. Dis.
(2005) - et al.
Striatal and cortical neurochemical changes induced by chronic metabolic compromise in the 3-nitropropionic model of Huntington's disease
Neurobiol. Dis.
(2002) - et al.
Replicating Huntington's disease phenotype in experimental animals
Prog. Neurobiol.
(1999) - et al.
Cannabinoid receptor messenger RNA levels decrease in a subset of neurons of the lateral striatum, cortex and hippocampus of transgenic Huntington's disease mice
Neuroscience
(2000) - et al.
Altered CB1 receptor and endocannabinoid levels precede motor symptom onset in a transgenic mouse model of Huntington's disease
Neuroscience
(2009) - et al.
Behavioural and molecular consequences of chronic cannabinoid treatment in Huntington's disease transgenic mice
Neuroscience
(2010) - et al.
Sertraline slows disease progression and increases neurogenesis in N171-82Q mouse model of Huntington's disease
Neurobiol. Dis.
(2008) - et al.
N-methyl-d-aspartate (NMDA) receptor function and excitotoxicity in Huntington's disease
Prog. Neurobiol.
(2007) - et al.
The pattern of neurodegeneration in Huntington's disease: a comparative study of cannabinoid, dopamine, adenosine and GABA(A) receptor alterations in the human basal ganglia in Huntington's disease
Neuroscience
(2000) - et al.
Delayed onset of Huntington's disease in mice in an enriched environment correlates with delayed loss of cannabinoid CB1 receptors
Neuroscience
(2004)
Loss of mRNA levels, binding and activation of GTP-binding proteins for cannabinoid CB1 receptors in the basal ganglia of a transgenic model of Huntington's disease
Brain Res.
The endocannabinoid pathway in Huntington's disease: a comparison with other neurodegenerative diseases
Prog. Neurobiol.
Localization of cannabinoid receptor in the human developing and adult basal ganglia. Higher levels in the striatonigral neurons
Neurosci. Lett.
Tiagabine is neuroprotective in the N171-82Q and R6/2 mouse models of Huntington's disease
Neurobiol. Dis.
A2A receptor knockout worsens survival and motor behaviour in a transgenic mouse model of Huntington's disease
Neurobiol. Dis.
Molecular and behavioral analysis of the R6/1 Huntington's disease transgenic mouse
Neuroscience
The cannabinoid receptor agonist WIN 55,212-2 attenuates the effects induced by quinolinic acid in the rat striatum
Neuropharmacology
Role of brain-derived neurotrophic factor in Huntington's disease
Prog. Neurobiol.
Mechanisms of neuronal death in Huntington's disease. First part: general considerations and histopathological features
Rev. Méd. Brux.
Mechanisms of neuronal death in Huntington's disease. Second part: therapeutic challenges
Rev. Méd. Brux.
Loss of striatal type 1 cannabinoid receptors is a key pathogenic factor in Huntington's disease
Brain
A dual role of adenosine A2A receptors in 3-nitropropionic acid-induced striatal lesions: implications for the neuroprotective potential of A2A antagonists
J. Neurosci.
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2019, NeuropharmacologyCitation Excerpt :In contrast, the pool of CB1 receptors located on corticostriatal projections remains unaffected along HD progression (Chiodi et al., 2012; Chiarlone et al., 2014). Of note, in the context of cannabinoid-evoked neuroprotection, we (Blazquez et al., 2011, 2015) and others (Mievis et al., 2011; Naydenov et al., 2014b) have demonstrated a neuroprotective role of the CB1 receptor in transgenic HD mice, an effect that is also evident in animal models of striatal excitotoxicity (Fernandez-Ruiz et al., 2011). For example, double-mutant mice expressing mutant huntingtin exon 1 in a CB1−/- background show an overt HD-like phenotype at earlier ages than their single-mutant littermates expressing mutant huntingtin exon 1 in a normal CB1+/+ background (Blazquez et al., 2011; Mievis et al., 2011).
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These authors equally contributed to this work.