Altered striatal endocannabinoid signaling in a transgenic mouse model of spinocerebellar ataxia type-3

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.

Effect of acute physical exercise on motor sequence memory

“…The hippocampus is not the only brain region modulated by CB1 activity. Recent studies have shown that CB1 activity protects striatal neurons in culture against excitotoxicity 18 while CB1 activity is reduced in striatal neurons in a mouse-model of ataxia 19 . Consistent with enhanced striatal function, one report indicated that acute physical exercise also improved procedural memory in a visuomotor accuracy tracking task in a dose–response manner, with higher exercise intensity significantly more beneficial than lower intensity 20 .…”

Effect of acute physical exercise on motor sequence memory

“…The hippocampus is not the only brain region modulated by CB1 activity. Recent studies have shown that CB1 activity protects striatal neurons in culture against excitotoxicity 18 while CB1 activity is reduced in striatal neurons in a mouse-model of ataxia 19 .…”

Endocannabinoid System in Spinocerebellar Ataxia Type-3 and Other Autosomal-Dominant Cerebellar Ataxias: Potential Role in Pathogenesis and Expected Relevance as Neuroprotective Targets

“…Such non-cerebellar signs (e.g., limb clasping as a sign of dystonia) may also be reproduced in experimental models of SCA-3 and associated with the changes in the endocannabinoid system in the striatum. Thus, in a second study carried out in SCA-3 transgenic mice (Rodríguez-Cueto et al, 2017; see Table 2 for a summary of those changes in endocannabinoid elements seen in the striatum of SCA-3 transgenic mice), we detected a reduction of CB 1 receptor levels associated with an elevation of FAAH levels in the striatum of SCA-3 transgenic mice. The reduction of CB 1 receptor levels was found in both striatal afferent and efferent neurons—in this last case, being associated with the losses of striatal projection neurons found in the SCA-3 transgenic mice (Rodríguez-Cueto et al, 2017).…”

“…Thus, in a second study carried out in SCA-3 transgenic mice (Rodríguez-Cueto et al, 2017; see Table 2 for a summary of those changes in endocannabinoid elements seen in the striatum of SCA-3 transgenic mice), we detected a reduction of CB 1 receptor levels associated with an elevation of FAAH levels in the striatum of SCA-3 transgenic mice. The reduction of CB 1 receptor levels was found in both striatal afferent and efferent neurons—in this last case, being associated with the losses of striatal projection neurons found in the SCA-3 transgenic mice (Rodríguez-Cueto et al, 2017). As will be discussed below, reductions in CB 1 receptor signaling may obviously aggravate excitotoxicity, which may explain the losses of striatal projection neurons in these mice, a fact also aggravated by the elevation detected in the FAAH enzyme also in the striatum, which would eventually reduce the levels of endocannabinoid ligands acting at the CB 1 receptor (Rodríguez-Cueto et al, 2017).…”

“…Only a few recent studies have investigated whether specific elements of the endocannabinoid system are altered in CNS structures that have been associated with the clinical signs of SCAs, namely the cerebellum, brainstem, and basal ganglia (Rodríguez-Cueto et al, 2014a,b, 2016, 2017). As mentioned above, to investigate this possibility is important both for elucidating whether these alterations may contribute to SCA pathogenesis and for developing potential cannabinoid-based therapies that may correct these signs, and eventually, to delay/arrest disease progression in SCAs.…”