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00925njm 22002777a 4500 dc Rodríguez Cueto, Carmen Aurora author Hernández-Gálvez, Mariluz author Hillard, Cecilia author Maciel, Patricia author García-García, Luis author Valdeolivas, Sara author Pozo García, Miguel Ángel author Ramos Atance, José Antonio author Gómez Ruiz, María Sagrario author Fernández Ruiz, José Javier author García García, Luis author 2016 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. 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. 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. doi: 10.1016/j.neuroscience.2016.09.046. Epub 2016 Oct 4. PMID: 27717809. 0306-4522 10.1016/j.neuroscience.2016.09.046 https://hdl.handle.net/20.500.14352/93390 https://doi.org/10.1016/j.neuroscience.2016.09.046 27717809 Dysregulation of the endocannabinoid signaling system in the cerebellum and brainstem in a transgenic mouse model of spinocerebellar ataxia type-3