Genetic analysis of striatal glutamate -dopamine interactions.

摘要

The induction of complex behaviors often requires coordinated signaling through various neurotransmitter systems. Within the basal ganglia, a group of nuclei that contribute to the control of locomotor behaviors, neurons receive input from many other brain regions. Descending projections from the cortex provide glutamatergic input to regions of the striatum while ascending projections from the brainstem provide dopaminergic input. Striatal neurons contain receptors for both glutamate and dopamine, providing anatomical evidence that these two systems act in concert to signal through these neurons. A great deal of work has examined how the signaling on striatal neurons by both glutamate and dopamine contribute to many different conditions, including Parkinson's disease, schizophrenia and drug addiction. In this dissertation, two lines of genetically modified mice, one engineered to lack dopamine and one which contains a mutant glutamate receptor on the cells that contain dopamine receptors, are used to further explore the interaction between glutamate and dopamine. Using mice that lack dopamine, it is shown that in the absence of dopamine, the locomotor behavior induced by increases in extracellular glutamate is not any different than in normal animals. Further, restoration of dopamine causes a synergistic increase in locomotor behavior, suggesting that when present, dopamine can contribute to the locomotor-inducing effect of drugs that increase extracellular glutamate. Using the mice that express a mutant NMDA receptor, it is shown that changes in glutamate signaling in neurons that contain dopamine receptors does not cause changes in basal locomotor activity or the acute response to drugs that affect dopamine signaling. However, drug-induced behaviors that require long-term neuronal changes are blunted in these mice. Together, these results indicate that while both the glutamate and dopamine signaling pathways are normally active in contributing to locomotor behaviors, when signaling is absent or altered in one system, the other system is mostly able to induce normal behaviors. However, certain behaviors that require not only acute drug effects, but also long-term changes do seem to require normal signaling through both systems.