Spinocerebellar ataxia (SCA1) is a polyglutamine-induced neurodegenerative disorder primarily caused by dysfunction in Purkinje cells of the cerebellum. Abnormalities in the physiological events underlying SCA1 disease pathology remain unclear. Especially problematic is the lack of insight into the mechanisms responsible for causing behavioral deficits to occur before neuronal loss. The SCA1[82Q] mouse is a model of SCA1 that conditionally expresses full-length human mutant ataxin-1 protein (ATXN1[82Q]) and recapitulates several hallmarks of the human disease, including progressive cerebellar dysfunction and Purkinje cell (PC) loss. The benefits of using this animal for SCA1 research are that it provides a regulable system that allows for examination of underlying disease processes, as well as behavioral, anatomical, and physiological recovery. Preliminary experiments utilizing the intrinsic flavoprotein autofluorescence signal examined the two major afferent circuits in the cerebellum, granule cell-parallel fiber and inferior olive-climbing fiber. Interestingly, our results indicate no functional difference in parallel fiber-Purkinje cell synaptic transmission through 20 weeks of age. Conversely, abnormalities were observed in the response pattern elicited in the cerebellar cortex to climbing fiber excitation. These results suggest that there is some specificity in the alteration of the cerebellar circuitry in the SCA1 disease state. Consequently, two hypotheses have been formed. One, there are alterations in the CF-PC circuitry in SCA1[82Q] mice. Two, expression of the SCA1[82Q] gene product, ataxin-1 [82Q] (ATXN1[82Q]), impairs CF-PC development. I will use flavoprotein autofluorescence imaging in the cerebellum of conditional SCA1[82Q] mice to further address abnormalities in the functioning of the CF-PC circuitry. Imaging and histological studies will then be used to determine the extent of recovery possible in the cerebellar circuitry when the mutant SCA1 gene is off during cerebellar development and then on. These studies intend to expand our knowledge of the pathophysiological events underlying SCA1 disease progression. Increased understanding of the mechanisms that lead to this disease will have implications for other members of the trinucleotide repeat disease class, and could aid in the identification of potential therapeutic targets.
|Ebner, Blake A; Ingram, Melissa A; Barnes, Justin A et al. (2013) Purkinje cell ataxin-1 modulates climbing fiber synaptic input in developing and adult mouse cerebellum. J Neurosci 33:5806-20|
|Barnes, Justin A; Ebner, Blake A; Duvick, Lisa A et al. (2011) Abnormalities in the climbing fiber-Purkinje cell circuitry contribute to neuronal dysfunction in ATXN1[82Q] mice. J Neurosci 31:12778-89|
|Duvick, Lisa; Barnes, Justin; Ebner, Blake et al. (2010) SCA1-like disease in mice expressing wild-type ataxin-1 with a serine to aspartic acid replacement at residue 776. Neuron 67:929-35|