Glutamate transport is essential for the synaptic inactivation of the neurotransmitter glutamate. A family of glutamate transporters has been identified in both astroglia and neurons. These transporters play important roles in the pathophysiology of neurologic disorders, notably ALS and Alzheimers disease. EAAT4 is a glutamate transporter selectively localized to cerebellar Purkinje cells and has the properties of a ligand-gated chloride ion channel. Its role in cerebellar physiology and in the possible pathogenesis of ataxic disorders is unknown. In this proposal, experiments are presented to study EAAT4 in Purkinje cell biology with larger implications for disorders to which EAAT4 dysfunction may contribute. First, a technique for the establishment of organotypic cerebellar cultures will be developed. These cultures will maintain their in vivo architecture and express the glutamate transporters, including EAAT4, that are present in the cerebellum. This system will allow the ability to manipulate conditions and assess factors that affect this glutamate transporter. Second, the phenotype that results from molecular knockdown of EAAT4 will be studied along with the neuroanatomical and neurophysiological changes in the cerebellum that accompany this reduction in protein expression. Finally, I will study whether EAAT4 dysfunction contributes to Purkinje cell death in the SCA1 transgenic mouse; a model for the human neurodegenerative disorder spinocerebellar ataxia.
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