Abstract
Spinocerebellar ataxia type 1 (SCA1) is an inherited progressive neurodegenerative movement disorder currently with no treatment. SCA1 is caused by an unstable CAG trinucleotide repeat in the mutant ataxin-1 gene. Understanding the major signalling mechanism underlying SCA1 is critical for the development of new therapeutic targets against this debilitating disorder.
Metabotropic glutamate receptor type-1 (mGluR1) is highly expressed in the Purkinje neurons (PN), the sole output neurons of the cerebellar cortex and regulates multiple synaptic plasticity mechanisms in the PN that are critical for cerebellar dependent motor learning. Consistent with this both loss or gain of mGluR1 signalling causes ataxia. Recent work has implicated both enhancing/decreasing mGluR1 signalling as a potential therapeutic target to treat SCA1. Thus, a better understanding of mGluR1 signalling in SCA1 is critical to translate these significant pre-clinical findings.
The aim of this study is to investigate the role of mGluR1 signalling in SCA1 disease progression. To achieve this we used a PN-specific SCA1 mouse model (SCA1 82Q) expressing the mutant ataxin-1 gene with an expanded 82 CAG repeat and we chronically manipulated mGluR1 signalling using mGluR1-specific allosteric modulators.
SCA1 82Q mice exhibit motor performance deficits at 4 weeks (early stage) that worsened with age and become more prominent at 12 weeks of age (midstage) in comparison with age-matched WT controls. Climbing fibre (CF) extension on the PN dendrite was reduced at an early stage of the disease, and a decrease in molecular layer height (MLH) was evident only at the midstage of disease.
Enhancing mGluR1 signalling chronically by treating with an mGluR1-specific positive allosteric modulator (PAM) from 4 weeks of age made WT mice ataxic. CF extension, PN simple spike firing frequency, and precision was also reduced in these mice. Enhancing mGluR1 signalling chronically from early to midstage worsened the SCA1 82Q motor phenotype and decreased PN simple spike firing precision. MLH, CF extension and PN simple spike firing frequency remained disrupted after mGluR1 PAM treatment in SCA1 82Q mice. Next, we investigated the influence of decreasing mGluR1 signalling by administering mGluR1 negative allosteric modulator (NAM) to midstage SCA1 82Q mice. Decreasing mGluR1 signalling rescued PN simple spike firing frequency and CF extension, but not the motor performance in these mice. Finally, we also provide evidence for altered KCC2 expression in SCA1 and mGluR1 PAM treated WT mice that probably mediates the paradoxical decrease in PN firing frequency observed after overactivation of excitatory mGluR1 receptors.
Overall this thesis provides evidence that chronic mGluR1 positive modulation recapitulates elements of SCA1 type ataxia and is detrimental for SCA1 progression. In contrast, mGluR1 negative modulation improves some of the cardinal features of SCA1.