Ataxic Symptoms in Huntington’s Disease Transgenic Mouse Model Are Alleviated by Chlorzoxazone

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.

A Chlorzoxazone‐Baclofen Combination Improves Cerebellar Impairment in Spinocerebellar Ataxia Type 1

“…Notably, chlorzoxazone treatment has also been shown to improve aberrant Purkinje neuron spiking and motor performance in other murine models of cerebellar ataxia. 37,[39][40][41] However, a combination of chlorzoxazone-baclofen has not been tested in rodent models of polyglutamine ataxia other than SCA1, although a related genetic strategy of viral BK channel replacement improves Purkinje neuron physiology in SCA7. 4 It is tempting to speculate that a shared mechanism of dysfunction exists across multiple etiologies of SCA and that a treatment strategy such as chlorzoxazone-baclofen may therefore have wider relevance for targeting cerebellar motor impairment.…”

“…Therefore, it is possible that chlorzoxazone‐baclofen may have relevance for treating motor impairment beyond SCA1. Notably, chlorzoxazone treatment has also been shown to improve aberrant Purkinje neuron spiking and motor performance in other murine models of cerebellar ataxia 37,39‐41 . However, a combination of chlorzoxazone‐baclofen has not been tested in rodent models of polyglutamine ataxia other than SCA1, although a related genetic strategy of viral BK channel replacement improves Purkinje neuron physiology in SCA7 4 .…”

Targeted therapy improves cellular dysfunction, ataxia, and seizure susceptibility in a model of a progressive myoclonus epilepsy

“…After two training sessions at a set speed, mice were tested on the accelerating rotarod, which revealed progressive deficits in performance in H/+ mice relative to +/+ ( Figures 3 D and 3E). In the elevated beam walk test, 31 H/+ mice made more errors in hind paw placement compared to age-matched +/+ littermates at both 4 and 6 months of age ( Figure 3 G).

Figure 3 H/+ mice exhibit age-related motor dysfunction and seizure susceptibility (A and B) At 6 months of age, H/+ mice exhibit a severe hindlimb clasping phenotype (A) with longer bouts of clasping (B).

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Structure–Activity Relationship Study of Subtype-Selective Positive Modulators of KCa2 Channels

“…Recordings of spontaneous PC activity from WT and SCA2-58Q mice at 7–8 months of age were performed as previously described. ,, Briefly, the mice were anesthetized with 2000 mg/kg urethane and transcardially perfused with ice-cold aCSF containing (mM) 85 NaCl, 24 NaHCO 3 , 25 glucose, 2.5 KCl, 0.5 CaCl 2 , 4 MgCl 2 , 1 NaH 2 PO 4 , and 75 sucrose. Solutions were equilibrated with carbogen (95% O 2 /5% CO 2 ).…”