Faculty Collaboration Database

Altered striatal endocannabinoid signaling in a transgenic mouse model of spinocerebellar ataxia type-3. PLoS One 2017;12(4):e0176521

Date

04/28/2017

Pubmed ID

28448548

Pubmed Central ID

PMC5407801

DOI

10.1371/journal.pone.0176521

Scopus ID

2-s2.0-85018275217 (requires institutional sign-in at Scopus site)   5 Citations

Abstract

Spinocerebellar ataxia type-3 (SCA-3) is the most prevalent autosomal dominant inherited ataxia. We recently found that the endocannabinoid system is altered in the post-mortem cerebellum of SCA-3 patients, and similar results were also found in the cerebellar and brainstem nuclei of a SCA-3 transgenic mouse model. Given that the neuropathology of SCA-3 is not restricted to these two brain regions but rather, it is also evident in other structures (e.g., the basal ganglia), we studied the possible changes to endocannabinoid signaling in the striatum of these transgenic mice. SCA-3 mutant mice suffer defects in motor coordination, balance and they have an abnormal gait, reflecting a cerebellar/brainstem neuropathology. However, they also show dystonia-like behavior (limb clasping) that may be related to the malfunction/deterioration of specific neurons in the striatum. Indeed, we found a loss of striatal projecting neurons in SCA-3 mutant mice, accompanied by a reduction in glial glutamate transporters that could potentially aggravate excitotoxic damage. In terms of endocannabinoid signaling, no changes in CB2 receptors were evident, yet an important reduction in CB1 receptors was detected by qPCR and immunostaining. The reduction in CB1 receptors was presumed to occur in striatal afferent and efferent neurons, also potentially aggravating excitotoxicity. We also measured the endocannabinoid lipids in the striatum and despite a marked increase in the FAAH enzyme in this area, no overall changes in these lipids were found. Collectively, these studies confirm that the striatal endocannabinoid system is altered in SCA-3 mutant mice, adding to the equivalent changes found in other strongly affected CNS structures in this type of ataxia (i.e.: the cerebellum and brainstem). These data open the way to search for drugs that might correct these changes.

Author List

Rodríguez-Cueto C, Hernández-Gálvez M, Hillard CJ, Maciel P, Valdeolivas S, 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

Animals
Disease Models, Animal
Endocannabinoids
Machado-Joseph Disease
Male
Mice
Mice, Transgenic
Neostriatum
Signal Transduction