The aim of this work is to study the convergence of dopaminergic and glutamatergic pathways in the mouse striatum, and how this convergence is significant to the study of schizophrenia. The first study examines the role of these dopamine receptors in the modulation of NMDA receptor (NMDAR) activity. The impact of elevated dopamine in DAT-deficient mice will be examined in the context of changes in dopamine receptor signaling pathways and how this ultimately alters NMDA receptor function. The second study examines the possibility of adaptive changes in dopamine receptor biology when NMDA receptor activity is altered. Dopamine receptor number and activity will be assessed in NMDA receptor deficient mice using neurochemistry and behavioral pharmacology. Together these studies may help to clarify the nature of glutamete/dopamine interactions in the striatum. The third study requires the generation of a transgenic mouse line with a striatum-specific deficiency in NMDA receptors. These mice will be used to study the role of the striatum in the elaboration of behaviors related to schizophrenia. The locomotor activity, social behavior, and cognitive abilities of these mice will be assessed and compared to the existing genetic and pharmacological models of schizophrenia. The response of mutant mice to antipsychotics will be examined, and the status of dopamine receptors and receptor signaling will be examined by biochemical methods in striatum and frontal cortex.
