Progressive impairment of cerebellar mGluR signalling and its therapeutic potential for cerebellar ataxia in spinocerebellar ataxia type 1 model mice

Abstract

Key pointsr Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease caused by a gene defect, leading to movement disorder such as cerebellar ataxia.r It remains largely unknown which functional defect contributes to the cerebellar ataxic phenotype in SCA1.r In this study, we report progressive dysfunction of metabotropic glutamate receptor (mGluR) signalling, which leads to smaller slow synaptic responses, reduced dendritic Ca 2+ signals and impaired synaptic plasticity at cerebellar synapses, in the early disease stage of SCA1 model mice.r We also show that enhancement of mGluR signalling by a clinically available drug, baclofen, leads to improvement of motor performance in SCA1 mice. r SCA1 is an incurable disease with no effective treatment, and our results may provide mechanistic grounds for targeting mGluRs and a novel drug therapy with baclofen to treat SCA1 patients in the future.Abstract Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease that presents with cerebellar ataxia and motor learning defects. Previous studies have indicated that the pathology of SCA1, as well as other ataxic diseases, is related to signalling pathways mediated by the metabotropic glutamate receptor type 1 (mGluR1), which is indispensable for proper motor coordination and learning. However, the functional contribution of mGluR signalling to SCA1 pathology is unclear. In the present study, we show that SCA1 model mice develop a functional impairment of mGluR signalling which mediates slow synaptic responses, dendritic Ca 2+ signals, and short-and long-term synaptic plasticity at parallel fibre (PF)-Purkinje cell (PC) synapses in a progressive manner from the early disease stage (5 postnatal weeks) prior to PC death. Notably, impairment of mGluR-mediated dendritic Ca 2+ signals linearly correlated with a reduction of PC capacitance (cell surface area) in disease progression. Enhancement of mGluR signalling by baclofen, a clinically available GABA B receptor agonist, led to an improvement of motor performance in SCA1 mice and the improvement lasted ß1 week after a single application of baclofen. Moreover, the restoration of motor performance in baclofen-treated SCA1 mice matched the functional recovery of mGluR-mediated slow synaptic currents and mGluR-dependent short-and long-term synaptic plasticity. These results suggest that impairment of synaptic mGluR cascades is one of the important contributing factors to cerebellar ataxia in early and middle stages of SCA1 pathology, and that modulation of mGluR signalling by baclofen or other clinical interventions may be therapeutic targets to treat SCA1. , human Ataxin-1 with 76 uninterrupted glutamine repeats; BDNF, brainderived neurotrophic factor; Calbindin, calbindin D-28k; C57BL/6 mice, C57 black 6 mice; CF, climbing fibre; CPCCOEt, 7-hydroxyiminocyclopropan[b]chromen-1a-carboxylate ethyl ester; ER, endoplasmic reticulum; D-AP5, D-(-)-2-amino-5-phosphonopentanoic acid; GFP, green fluorescent protein; GPCR, G-protein-coupled rec...

Type-1 metabotropic glutamate receptor signaling in cerebellar Purkinje cells in health and disease

“…Power et al reported that blockade of astroglial glutamate transporters, which markedly enhances the amplitude and the duration of mGluR1-mediated slow EPSPs in control mice, had no effect in the SCA1 82Q mouse line 84 . This result suggests that glutamate uptake by Bergmann glia may be severely impaired in the SCA1 82Q mouse line used by Power et al and, therefore, mGluR1-mediated slow EPSPs may be prolonged, even though mGluR1 signaling itself might be impaired in Purkinje cells similarly to those of the SCA1 Tg-B05 line used by Shuvaev et al 81 …”

“…Power et al recently reported that the SCA1 82Q mouse line generated by Zu et al 79 , which is different from the SCA1 Tg-B05 line originally generated by Burright et al 72 and used in the recent study by Shuvaev et al 81 , exhibits reduced motor performance in the rotating rod, reduced complexity of Purkinje cell outer dendrites, decreased height of climbing fiber innervation, and lower frequency of Purkinje cell simple spike firing at 12 weeks of age 84 ( Table 2). In contrast to the report by Shuvaev et al 81 , mGluR1-mediated slow EPSCs and local Ca 2+ transients in dendrites induced by repetitive parallel fiber stimulation were both prolonged in SCA1 82Q Purkinje cells without significant changes in their amplitudes 84 . Remarkably, administration of a negative allosteric modulator (NAM) of mGluR1 shortened the two forms of mGluR1-mediated synaptic responses and ameliorated the ataxia 84 .…”

“…Very recently, Shuvaev et al 81 reported that the SCA1 82Q mouse line (SCA1-Tg; heterozygous B05 line carrying the human Ataxin-1 gene with 82 Q repeats under the control of the Purkinje cell-specific L7 promoter) generated by Burright et al 72 exhibited progressive ataxia and impairment in multiple mGluR1 signaling at parallel fiber–Purkinje cell synapses from postnatal week 5 to 12, including TRPC3-mediated slow EPSCs, IP 3 -mediated local Ca 2+ signaling in Purkinje cell dendrites, endocannabinoid-mediated short-term synaptic depression, and LTD 81 ( Table 1). Importantly, intraperitoneal administration of a GABA B R agonist, baclofen, restored mGluR1 signaling at parallel fiber–Purkinje cell synapses and ameliorated ataxia of the SCA1 82Q mouse 81 .…”

“…Importantly, intraperitoneal administration of a GABA B R agonist, baclofen, restored mGluR1 signaling at parallel fiber–Purkinje cell synapses and ameliorated ataxia of the SCA1 82Q mouse 81 . These results are relevant to the in vitro studies by Kamikubo et al 57 and raise the possibility of a new therapy for SCA1, since baclofen is a clinically available drug 81 .…”

“…Given that the recent development of mGluR1 PAM and NAM have raised the possibility of treating cerebellar ataxias, it is important to determine whether mGluR1 signaling is up- or down-regulated at a particular stage of cerebellar ataxia. In addition, a very recent report suggests that baclofen, a clinically available GABA B R agonist, can ameliorate cerebellar dysfunction by enhancing mGluR1 signaling in a SCA1 model mouse line 81 . Careful examination of the mouse models with the progress of cerebellar symptoms would be necessary.…”