The endocannabinoid system is affected by cholesterol dyshomeostasis: Insights from a murine model of Niemann Pick type C disease

Neurobiology of Disease

Cinzia Rapino¹  Paola Caporali²  Antonio Totaro³  Mauro Maccarrone³  Jessica Dragotto³  Lucia Scipioni³  Maria Teresa Fiorenza⁴  Cristina Orsini⁴  Sergio Oddi⁴  Sonia Canterini⁵  Marzia Maiolati⁵  Clotilde Beatrice Angelucci⁵ 

[1] Department of Psychology, Division of Neuroscience and “Daniel Bovet” Neurobiology Research Center, Sapienza University of Rome, Via dei Sardi 70, 00185 Rome, Italy;Fondazione Santa Lucia, IRCCS, Via del Fosso di Fiorano 64, 00179, Italy;Department of Psychology, Division of Neuroscience and “Daniel Bovet” Neurobiology Research Center, Sapienza University of Rome, Via dei Sardi 70, 00185 Rome, Italy;Faculty of Veterinary Medicine, University of Teramo, Teramo, Italy;Fondazione Santa Lucia, IRCCS, Via del Fosso di Fiorano 64, 00179, Italy;

关键词: Lysosomal storage disorders;    Genetic mouse models;    Endocannabinoid system biochemistry;    Behavioral phenotyping;   

DOI  :  

来源: DOAJ

【 摘 要 】

The dyshomeostasis of intracellular cholesterol trafficking is typical of the Niemann-Pick type C (NPC) disease, a fatal inherited lysosomal storage disorder presenting with progressive neurodegeneration and visceral organ involvement. In light of the well-established relevance of cholesterol in regulating the endocannabinoid (eCB) system expression and activity, this study was aimed at elucidating whether NPC disease-related cholesterol dyshomeostasis affects the functional status of the brain eCB system. To this end, we exploited a murine model of NPC deficiency for determining changes in the expression and activity of the major molecular components of the eCB signaling, including cannabinoid type-1 and type-2 (CB1 and CB2) receptors, their ligands, N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), along with their main synthesizing/inactivating enzymes. We found a robust alteration of distinct components of the eCB system in various brain regions, including the cortex, hippocampus, striatum and cerebellum, of Npc1-deficient compared to wild-type pre-symptomatic mice. Changes of the eCB component expression and activity differ from one brain structure to another, although 2-AG and AEA are consistently found to decrease and increase in each structure, respectively. The thorough biochemical characterization of the eCB system was accompanied by a behavioral characterization of Npc1-deficient mice using a number of paradigms evaluating anxiety, locomotor activity, spatial learning/memory abilities, and coping response to stressful experience. Our findings provide the first description of an early and region-specific alteration of the brain eCB system in NPC and suggest that defective eCB signaling could contribute at producing and/or worsening the neurological symptoms of this disorder.

【 授权许可】

Unknown