Abstract
Huntington’s disease (HD) is a hereditary neurodegenerative disease caused by a polyglutamine expansion in the huntingtin protein, Striatum atrophy in HD leads to a progressive disturbance of psychiatric, motor, and cognitive function. Recent studies of HD patients revealed that the degeneration of cerebellum is also observed independently from the striatal atrophy during early HD stage and may contribute to the motor impairment and ataxia observed in HD. Cerebellar Purkinje cells (PCs) are responsible for the proper cerebellar pathways functioning and motor control. Recent studies on mouse models of HD have shown that the abnormality of the biochemical functions of PCs are observed in HD, suggesting the contribution of PC dysfunction and death to the impaired movement coordination observed in HD. To investigate ataxic symptoms in HD we performed a series of experiments with the yeast artificial chromosome transgenic mouse model of HD (YAC128). Using extracellular single-unit recording method we found that the portion of the cerebellar PCs with bursting and irregular patterns of spontaneous activity drastically rises in aged YAC128 HD mice when compared with wild type littermates. Previous studies demonstrated that SK channels are responsible for the cerebellar PC pacemaker activity and that positive modulation of SK channel activity exerted beneficial effects in different ataxic mouse models. Here we studied effects of the SK channels modulator chlorzoxazone (CHZ) on the motor behavior of YAC128 HD mice and also on the electrophysiological activity and neuroanatomy of the cerebellar PCs from these mice. We determined that the long-term intraperitoneal injections of CHZ alleviated the progressive impairment in the firing pattern of YAC128 PCs. We also demonstrated that treatment with CHZ rescued age-dependent motor incoordination and improved the cerebellar morphology in YAC128 mice. We propose that abnormal changes in the PC firing patterns might be a one of the possible causes of ataxic symptoms in HD and in other polyglutamine disorders and that the pharmacological activation of SK channels may serve as a potential way to improve the activity of cerebellar PCs and relieve the ataxic phenotype in HD patients.
Highlights
Huntington’s disease (HD) represents an autosomal dominant neurodegenerative disease that initially presents itself in patients aged 35–50 years old that unrelentingly leads to the patient’s death within 15–20 years after the initial manifestation
We discovered that the mean Purkinje cells (PCs) simple spike (SS) firing frequency (FF) was similar in 6-monthold YAC128 mice and their WT littermates, but was significantly reduced in 9-month-old YAC128 HD mice (Figure 1C)
We further discovered that the average post-complex spike (CS) pause in the PC discharge was similar in 6-month-old YAC128 mice and their WT littermates, but was significantly increased in 9-month-old YAC128 HD mice (Figure 1E)
Summary
Huntington’s disease (HD) represents an autosomal dominant neurodegenerative disease that initially presents itself in patients aged 35–50 years old that unrelentingly leads to the patient’s death within 15–20 years after the initial manifestation. The disease-causing gene is HTT with extra CAG repeats coding for the huntingtin protein (htt) with an excessive polyglutamine (polyQ) expansion in the N-terminal domain (The huntington’s disease collaborative research group, 1993). The htt has more than 35 Q residues in HD. The htt protein is ubiquitously translated in the brain and other areas and the level of its translation in the striatum is similar to the other areas of the brain and body (Li et al, 1993). Htt has an important role in the ontogenesis and the HTT deletion leads to the prenatal death in mice (Nasir et al, 1995). Htt has many other functions, but the pathological pathway of the mutant htt still remains unclear (Saudou and Humbert, 2016)
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