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...

No abstract

No abstract

An experiment with a newly developed high-resolution kaon spectrometer (HKS) and a scattered electron spectrometer with a novel configuration was performed in Hall C at Jefferson Lab (JLab). The ground state of a neutron-rich hypernucleus,

In order to study the Σ-nucleus optical potential, we measured inclusive (π − , K + ) spectra on medium-to-heavy nuclear targets: CH2, Si, Ni, In and Bi. The CH2 target was used to calibrate the excitation energy scale by using the elementary process p + π − → K + + Σ − , where the C spectrum was also extracted. The calibration was done with ±0.1 MeV precision. The angular distribution of the elementary cross section was measured, and agreed well with the previous bubble chamber data, but with better statistics, and the magnitudes of the cross sections of the measured inclusive (π − , K + ) spectra were also well calibrated. All of the inclusive spectra were found to be similar in shape at a region near to the Σ − binding energy threshold, showing a weak mass-number dependence on the magnitude of the cross section. The measured spectra were compared with a theoretical calculation performed within the framework of the Distorted Wave Impulse Approximation (DWIA). It has been demonstrated that a strongly repulsive Σ-nucleus potential with a non-zero size of the imaginary part is required to reproduce the shape of the measured spectra.

In order to produce a neutron-rich Lambda hypernucleus for the first time, we carried out an experiment by utilizing the (pi-,K+) double charge-exchange reaction on a 10B target. We observed the production of a 10LambdaLi hypernucleus. The cross section for the Lambda bound region was found to be 11.3+/-1.9 nb/sr with the 1.2 GeV/c incident momentum, which is compared with the 10LambdaB hypernucleus production cross section, 7.8+/-0.3 microb/sr, in the (pi+,K+) reaction with a 1.05 GeV/c incident momentum beam.