Postnatal development of the cerebellar circuitry in the KIKO mouse model of Friedreich’s ataxia

Early clinical features in FA patients include absence of reflexes, sensory loss, progressive ataxia, and weakness. Ataxia is attributable to impairments of sensory and cerebellar pathways. While these impairments have been considered the consequence of progressive degenerative events and neuronal loss over time, more recent studies point to a failure to properly develop for some of these structures. Cerebellar pathology, which is defined by atrophy of large neurons and synaptic degeneration, has been historically considered degenerative in nature. However, recent research has revealed that synaptic deficits and abnormal cerebellar circuitry may precede atrophy of large neurons in the cerebellum. Dr Magrane has shown that in a mouse model of FA, the macrostructure of the cerebellum seems to be normal, but his studies also indicate that cerebellar neurons could have abnormal physiology or altered circuit formation. Dr Magrane hypothesizes that these neurodevelopmental abnormalities affecting neuronal pathways in the cerebellum ultimately lead to neuronal degeneration. The goals of this project are to define the nature of cerebellar pathology using a mouse model of FA, to enable identification of the cell types that require FXN during either neurodevelopment or neurodegeneration or both in the cerebellum, and to provide insights into the functional integrity of the cerebellar circuitry. Determining the most vulnerable regions in the cerebellum affected by FXN deficiency and the mechanisms underlying neurodevelopment and neurodegeneration will be important for our understanding of the pathogenesis of FA and for planning future therapeutic strategies.