title: Dysregulation of the endocannabinoid signaling system in the cerebellum and brainstem in a transgenic mouse model of spinocerebellar ataxia type-3.
abstract: Spinocerebellar ataxia type-3 (SCA-3) is a rare disease but it is the most frequent type within the autosomal dominant inherited ataxias. The disease lacks an effective treatment to alleviate major symptoms and to modify disease progression. Our recent findings that endocannabinoid receptors and enzymes are significantly altered in the post-mortem cerebellum of patients affected by autosomal-dominant hereditary ataxias suggest that targeting the endocannabinoid signaling system may be a promising therapeutic option. Our goal was to investigate the status of the endocannabinoid signaling system in a transgenic mouse model of SCA-3, in the two CNS structures most affected in this disease - cerebellum and brainstem. These animals exhibited progressive motor incoordination, imbalance, abnormal gait, muscle weakness, and dystonia, in parallel to reduced in vivo brain glucose metabolism, deterioration of specific neuron subsets located in the dentate nucleus and pontine nuclei, small changes in microglial morphology, and reduction in glial glutamate transporters. Concerning the endocannabinoid signaling, our data indicated no changes in CB2receptors. By contrast, CB1receptors increased in the Purkinje cell layer, in particular in terminals of basket cells, but they were reduced in the dentate nucleus. We also measured the levels of endocannabinoid lipids and found reductions in anandamide and oleoylethanolamide in the brainstem. These changes correlated with an increase in the FAAH enzyme in the brainstem, which also occurred in some cerebellar areas, whereas other endocannabinoid-related enzymes were not altered. Collectively, our results in SCA-3 mutant mice confirm a possible dysregulation in the endocannabinoid system in the most important brain structures affected in this type of ataxia, suggesting that a pharmacological manipulation addressed to correct these changes could be a promising option in SCA-3.
authors.affiliation: Instituto Universitario de Investigación en Neuroquímica, Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Rodríguez-Cueto
authors.affiliation: Instituto Universitario de Investigación en Neuroquímica, Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain; Departamento de Psicobiología, Facultad de Psicología, Universidad Complutense, Madrid, Spain.
authors.forename: Mariluz
authors.initials: M
authors.lastname: Hernández-Gálvez
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Cecilia J
authors.initials: CJ
authors.lastname: Hillard
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimaraes, Portugal.
authors.forename: Patricia
authors.initials: P
authors.lastname: Maciel
authors.affiliation: Unidad de Cartografía Cerebral, Instituto Pluridisciplinar, Universidad Complutense, Madrid, Spain; Departamento de Farmacología, Facultad de Farmacia, Universidad Complutense, Madrid, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: García-García
authors.affiliation: Instituto Universitario de Investigación en Neuroquímica, Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Valdeolivas
authors.affiliation: Unidad de Cartografía Cerebral, Instituto Pluridisciplinar, Universidad Complutense, Madrid, Spain; Departamento de Fisiología, Facultad de Medicina, Universidad Complutense, Madrid, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Pozo
authors.affiliation: Instituto Universitario de Investigación en Neuroquímica, Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain.
authors.forename: José A
authors.initials: JA
authors.lastname: Ramos
authors.affiliation: Instituto Universitario de Investigación en Neuroquímica, Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain; Departamento de Psicobiología, Facultad de Psicología, Universidad Complutense, Madrid, Spain. Electronic address: msgr@med.ucm.es.
authors.forename: María
authors.initials: M
authors.lastname: Gómez-Ruiz
authors.affiliation: Instituto Universitario de Investigación en Neuroquímica, Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain. Electronic address: jjfr@med.ucm.es.
authors.forename: Javier
authors.initials: J
authors.lastname: Fernández-Ruiz
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D001933:Brain Stem / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D002531:Cerebellum / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D063388:Endocannabinoids / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D017827:Machado-Joseph Disease / Q000378:metabolism* / Q000473:pathology; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D063388:Endocannabinoids; D005947:Glucose; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D000099252:Fatty Acid Amide Hydrolases; C578453:CNR1 protein, mouse; C571431:Cnr2 protein, mouse
keywords: Machado-Joseph disease; autosomal-dominant inherited ataxias; cannabinoids; endocannabinoid signaling system; motor incoordination; spinocerebellar ataxia-3