The aim of the proposed research is to further our understanding of the way in which glutamatergic and dopaminergic synaptic transmission contribute to the function of the neostriatum. Previous experiments have demonstrated roles for both ionotropic and metabotropic glutamate receptors in corticostriatal synaptic transmission. In addition, two forms of synaptic depression (STD and LTD) have been observed at these synapses. Experiments are designed to determine: 1) The synaptic locus of alterations involved in striatal LTD; 2) The role of corticostriatal and nigrostriatal afferent inputs in eliciting striatal LTD; 3) The mechanisms involved in presynaptic modulation of transmission by metabotropic glutamate receptors. Glutamate or a related amino acid is the major excitatory neurotransmitter in the mammalian CNS. Within the caudate nucleus and putamen, glutamate- containing fibers from the cortex and possibly thalamus form synapses with neurons, most notably the medium spiny neurons. Activation of these synapses depolarizes striatal neurons which activates the neurons directly or increases the likelihood of their being activated by other inputs. A further understanding of the physiologic and pharmacologic properties of these synapses is critical to the appreciation of functional neostriatal circuitry. The dopaminergic nigrostriatal pathway also plays a prominent role in regulation of striatal function, and is critically involved in the neuropathology of Parkinson's disease and other neurological disorders involving the basal ganglia. However, relatively little is known about the consequences of activation of this pathway at the level of cellular physiology and synaptic transmission. It is our hypothesis that elucidation of the role of glutamatergic corticostriatal transmission and dopaminergic nigrostriatal transmission in striatal function will aid in the development of therapeutic approaches to disorders involving impairment of striatal function.
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