RT Journal Article
T1 Altered striatal endocannabinoid signaling in a transgenic mouse model of spinocerebellar ataxia type-3
A1 Hernández-Gálvez, Mariluz
A1 Hillard, Cecilia J.
A1 Maciel, Patricia
A1 Valdeolivas, Sara
A1 Rodríguez Cueto, Carmen Aurora
A1 Gómez Ruiz, María Sagrario
A1 Fernández Ruiz, José Javier
A1 Ramos Atance, José Antonio
A2 David R Borchelt, 
AB 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.
PB PLOS
SN 1932-6203
YR 2017
FD 2017-04-27
LK https://hdl.handle.net/20.500.14352/93218
UL https://hdl.handle.net/20.500.14352/93218
LA eng
DS Docta Complutense
RD 1 sept 2024