ETIOLOGIC PATHWAYS TO DOPAMINE DYSFUNCTION

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The premise of this Conte Center application is that cortical disruption of glutamatergic synaptic function is the final common pathway in schizophrenia, manifesting in schizophrenia-associated behaviors, a dopamine-imbalance endophenotypes and adolescent-onset aberrations in brain structure/function. The goal of this project is to generate mouse models with a plausible etiology, and to ask whether the models are associated with dopaminergic and glutamatergic abnormalities replicating those seen in patients undergoing brain imaging. The models are an example of timed disruption of cerebral cortical development, administration of the neuronal DNA-methylating agent methylazoxymethanol acetate (MAM) at gestational day 16, a linkage-validated neurodevelopmental model, the NRG1 heterozygote knockdown, and a subtle presynaptic cortical glutamatergic deficit, a restricted knockdown or knockout of the glutamate-synthetic enzyme phosphate-activated glutaminase. These mechanistically distinct mouse models will be studied in concert with the goal of identifying: Aim 1. Dopamine system alterations, looking at the behavioral response to dopaminergic agonists in acute and sensitization paradigms, baseline and amphetamine-stimulated dopamine efflux in the striatum and frontal cortex using in vivo microdialysis, dopamine receptor expression, dopaminergic innervation of stereological quantification of tyrosine hydroxylase-positive fibers, and abnormalities in expression of genes regulated by dopamine in striatum and cortex. Aim 2. Glutamatergic alterations in cortex, looking at frontal-cortical dependent cognitive/behavioral functions, changes in gross morphology and activity using MRI, synapse-associated gene expression using microarray technology, NMDA receptor expression by rt-PCR and by ligand binding, and glutamatergic synaptic transmission and plasticity. Aim 3. glutamate receptor activation or direct stimulation of the frontal cortex affect dopamine neuron firing and dopamine efflux. Aim 4. Development of schizophrenia-associated alterations, looking at young mice prior to weaning and in adolescence, to verify adolescent onset of schizophrenia associated findings. Taken together, the mouse models in this Project together with those in Project by Kandel should identify a possible final common pathway in the pathogenesis of schizophrenia, which can be most effectively analyzed in mice with studies spanning behavior, chemistry, physiology and gene expression. As candidate genes can be validated by correlations with clinical data, new therapeutic directions should become evident.