The involvement of mGluR1 hyper-activation in the progression of cerebellar ataxia in SCA1 mice
|dc.contributor.author||Desai, Heena Nitin|
|dc.identifier.citation||Desai, H. N. (2014). The involvement of mGluR1 hyper-activation in the progression of cerebellar ataxia in SCA1 mice (Thesis, Bachelor of Biomedical Sciences with Honours). University of Otago. Retrieved from http://hdl.handle.net/10523/5252||en|
|dc.description.abstract||Spinocerebellar ataxia type 1 (SCA1) is an incurable, autosomal dominant progressive neurodegenerative disorder characterised by ataxia, progressive motor deterioration and selective neuronal loss in the cerebellum. It results from a CAG trinucleotide repeat expansion within the SCA1 gene product, ataxin-1. Metabotropic glutamate receptors type 1 (mGluR1) mobilise calcium from intracellular stores as part of their key role in cerebellar synaptic plasticity and motor learning and may be involved in the progression of ataxic symptoms. In this study, we use an 82Q transgenic mouse model of SCA1 where the CAG expansion is restricted to mouse cerebellar Purkinje neurons (PNs), the primary site of SCA1 pathology. This restricted expression in the PNs is achieved by tetracycline-controlled system. We use doxycycline to repress transgene expression at early (6 weeks) and mid (12 weeks) stages of the disease. Our aim is to use this model to identify potential mechanisms that contribute to the early stages of the progression of SCA1. We hypothesise that changes in mGluR1 expression underlie the progression from early pre-symptomatic to ataxia symptoms. Behavioural testing involved using an accelerating rotarod apparatus to assess motor performance and learning. 6 week old SCA1 transgenic mice exhibited mild ataxic motor symptoms (P < 0.01, two way ANOVA, n = 12) that progressed further at 12 weeks of age (P < 0.05, two way ANOVA, n = 7). Doxycycline treatment to repress the transgene expression prevented the mild ataxic symptoms at 6 weeks and reversed the progressively worse ataxic symptoms at 12 weeks of age. Immunohistochemistry experiments showed an increase in mGluR1 expression specifically in the molecular layer of 12 week old SCA1 mice (P < 0.05, two way ANOVA, n = 4). Doxycycline treatment did not prevent this enhanced expression of mGluR1, suggesting that enhanced mGluR1 expression may precede the onset of behavioural ataxia. Cell attached patch clamp recordings from PNs in SCA1 transgenic mice showed a decrease in instantaneous action potential (spike) firing frequency in comparison to PNs from FVB mice (P < 0.01, unpaired t-test with Welch’s correction, FVB: n = 3, SCA: n = 10). The application of Picrotoxin (PTX), a GABAA receptor antagonist resulted in: a non-significant trend towards an increase in instantaneous frequency and decrease in instantaneous firing irregularity of PNs from SCA1 mice. These data suggest a more powerful inhibitory influence in the cerebellar cortex of SCA1 mice compared with FVB mice. Overall, these results suggest that enhanced mGluR1 expression may disrupt PN calcium homeostasis leading to changes in PN firing and cerebellar output that drives the progression of SCA1. Our findings have important implications for the treatment of this rare but incurable human ataxia. The mGluR1 may be a potential therapeutic target for treating patients that are mildly symptomatic in the early stages of the disease.|
|dc.publisher||University of Otago|
|dc.rights||All items in OUR Archive are provided for private study and research purposes and are protected by copyright with all rights reserved unless otherwise indicated.|
|dc.title||The involvement of mGluR1 hyper-activation in the progression of cerebellar ataxia in SCA1 mice|
|thesis.degree.name||Bachelor of Biomedical Sciences with Honours|
|thesis.degree.grantor||University of Otago|
Files in this item
There are no files associated with this item.
This item is not available in full-text via OUR Archive.
If you are the author of this item, please contact us if you wish to discuss making the full text publicly available.