Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disorder caused by a polyglutamine expansion in the P/Q type voltage gated calcium channels (P/Q channels) in cerebellar Purkinje cells (Zhuchenko et al., 1997). A knock-in mouse model of SCA6 (SCA6 KI) was recently developed that recapitulates several key features of the human disease, including a delayed onset of disease symptoms (Watase et al., 2008). Given that P/Q channels play important roles in the development and function of Purkinje cells in the cerebellum, we wondered whether developmental abnormalities contribute to SCA6. To address this question, we are studying the developmental refinement of climbing fiber synapses onto Purkinje cells in SCA6 KI mice, since this well-characterised form of synapse elimination has been shown to depend on P/Q channel function (Hashimoto et al., 2011). During cerebellar development, Purkinje cells are normally innervated by multiple climbing fibers; synapse elimination occurs during the second postnatal week of development so that only one climbing fiber innervates each Purkinje cell by the third week of postnatal development. We observe that during the second postnatal week of development, a time when wildtype (WT) control Purkinje cells are normally innervated by only one or two climbing fibers, Purkinje cells from SCA6 KI mice are innervated by significantly more climbing fibers. These results suggest that climbing fiber synapse elimination is delayed in SCA6 KI mice. Given that multiple climbing fiber innervation in adult Purkinje cells is often associated with motor incoordination (Chen et al., 1995), our long-term goal is to dissect how altered brain development contributes to disease onset in SCA6.
Developmental Abnormalities in the Cerebellum in SCA6 KI Mice