Zebrin molecular identity and cerebellar location determine Purkinje cell vulnerability in Christianson syndrome mice

Abstract

Ataxia is a major characteristic feature in Christianson syndrome, where Purkinje cells in the anterior cerebellar vermis are vulnerable to degeneration while those in the posterior vermis are resilient. Here, we provide a temporal study of changes in Purkinje cell function, cell vulnerability and innervation of cerebellar nuclei in a mouse model of Christianson syndrome. Purkinje cells express certain molecules in a patterned manner across the cerebellum, such as aldolase C/zebrin-II (zebrin). We show that zebrin patterning appears normal before disease onset in Christianson syndrome mice with no apparent cell death, similar to what has been reported in patients. We observe rapid Purkinje cell death in the anterior lobe of Christianson syndrome mice that is exclusive to zebrin-negative Purkinje cells, with zebrin-positive Purkinje cells showing resilience. Intrinsic firing deficits exclusively in the anterior cerebellum are observed at the same time as the first observed cell death in the anterior cerebellum. In contrast, posterior Purkinje cells degenerated later, but zebrin-negative and zebrin-positive cells were equally susceptible to degeneration. Purkinje cells innervation in the cerebellar nuclei was also lost in Christianson syndrome mice in a region-specific manner: neurons in the anterior cerebellar nuclei, with predominantly zebrin-negative Purkinje cells inputs, displayed dramatic loss of Purkinje cells innervation, while neurons in the posterior cerebellar nuclei, innervated by both zebrin-negative and zebrin-positive terminals, showed greater resiliency. Together, our results highlight that cerebellar location and zebrin molecular identity appear important to the vulnerability of Purkinje cells and their innervation in the cerebellar nuclei in Christianson syndrome. HIGHLIGHTSO_LIFirst study showing Purkinje cell intrinsic firing alterations in Christianson syndrome mice. C_LIO_LIZebrin patterning appears normal before disease onset in Christianson syndrome mice. C_LIO_LIPurkinje cell firing deficits and death start at post-natal day 35 only in the anterior cerebellum in a Christianson syndrome mouse model. C_LIO_LIZebrin-negative and zebrin-positive Purkinje cells in the posterior cerebellum are initially resilient but are both equally susceptible to Purkinje cell death at later stages of the disorder. C_LIO_LIZebrin-negative Purkinje cell inputs to the anterior cerebellar nuclei are lost, while zebrin-positive inputs remain. C_LIO_LIThe pattern of Purkinje cell death in Christianson Syndrome is similar to that of many rare ataxias, suggesting a comparable underlying pathophysiology, which could lead to common therapeutic targets. C_LI