Mutations in the gene encoding b-III spectrin, highly expressed in Purkinje cells, lead to spinocerebellar ataxia type 5 (SCA5) and spectrin-associated autosomal recessive cerebellar ataxia type-1 (SPARCA1). Loss of b-III spectrin (b-III-/-) in mice has been shown to mirror the clinical phenotypes of both diseases and has revealed considerable Purkinje cell dysfunction prior to cell loss, including larger parallel fiber-Purkinje cell excitatory postsynaptic currents (PF-PC EPSCs). Reduction of the two most abundant cerebellar glutamate transporters (EAAT4 and GLAST) is also observed in b-III-/- mice, EAAT4 already reduced at 3 weeks of age, correlating with Purkinje cell hyperexcitability, whereas GLAST levels progressively drop from 3 months onwards. Involvement of these two glutamate transporters in cerebellar pathogenesis has been investigated using mice lacking either EAAT4 or GLAST. This has revealed that loss of EAAT4 can account for the initial hyperexcitability of Purkinje cells lacking b-III spectrin and that complete loss of either one of the two primary cerebellar glutamate uptake mechanisms is sufficient to cause progressive ataxia. However the physiological effect of either EAAT4 or GLAST loss on Purkinje cell activity and survival depends on the cells’ cerebellar localization. Furthermore, combined loss of EAAT4 and GLAST has been found to have a profound effect on Purkinje cells within the posterior cerebellum. The discovery that the posterior cerebellum is the first area affected pathologically in b-III-/- mice suggests an important role for this region in the pathogenesis of SCA5 and SPARCA1.