Faculty Collaboration Database

Dysregulation of the endocannabinoid signaling system in the cerebellum and brainstem in a transgenic mouse model of spinocerebellar ataxia type-3. Neuroscience 2016 Dec 17;339:191-209

Date

11/05/2016

Pubmed ID

27717809

DOI

10.1016/j.neuroscience.2016.09.046

Scopus ID

2-s2.0-84992735493 (requires institutional sign-in at Scopus site)   20 Citations

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 CB₂ receptors. By contrast, CB₁ receptors 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.

Author List

Rodríguez-Cueto C, Hernández-Gálvez M, Hillard CJ, Maciel P, García-García L, Valdeolivas S, Pozo MA, Ramos JA, Gómez-Ruiz M, Fernández-Ruiz J

Author

Cecilia J. Hillard PhD Associate Dean, Center Director, Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Amidohydrolases
Animals
Brain Stem
Cerebellum
Disease Models, Animal
Endocannabinoids
Glucose
Machado-Joseph Disease
Mice, Transgenic
Motor Activity
Neuroglia
Neurons
Phenotype
Receptor, Cannabinoid, CB1
Receptor, Cannabinoid, CB2