The MPTP-lesioned mouse serves as an excellent model to study the mechanisms involved in the return of striatal dopamine after basal ganglia injury. The administration of MPTP to C57BL/6 mice leads to the destruction of nigrostriatal dopaminergic neurons and subsequent depletion of striatal dopamine. An advantage of MPTP-lesioning is that the degree of neuronal cell death can be titrated such that remaining dopaminergic neurons may act as a template for repair and recovery in response to the injury. Our hypothesis is that glutamate, acting through altered expression of the AMPA-subtype of receptor, activates the transcription factor phospho-CREB and leads to increased tyrosine hydroxylase expression and axonal sprouting in surviving nigrostriatal dopaminergic neurons. This research proposal is designed to define changes that take place after MPTP injury in the expression of AMPA receptors (including their phosphorylated state), the transcription factor CREB, dopamine receptors (Dl, D2, and D3), and the growth-associated protein GAP-43. The effect of blocking glutamate neurotransmission with the AMPA receptor antagonist GYKI-52466 on these parameters will be determined. The molecular tools of immunocytochemistry, western immunoblotting, in situ hybridization, and anterograde labeling will be used to define the mechanisms involved in the return of striatal dopamine. The long-term goal of these studies is to elucidate features of plasticity following injury to the brain and to identify new therapeutic interventions for the treatment of neurodegenerative diseases including Parkinson's disease, Alzheimer's disease, and aging.
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