Project Summary

Stephen Rayport, M.D., Ph.D. (Independent Investigator 2003) of Columbia University, notes that schizophrenia is a complex disorder involving multiple genes in which an environmental insult during early development engenders a process capable of causing the disease in a genetically vulnerable individual. Many aspects of schizophrenia can be modeled in animals by reducing glutamatergic synaptic function. However, previous work has focused on postsynaptic receptors, and so has not identified the brain circuits most involved in the expression of schizophrenic symptoms. He therefore proposes to move from this regional localization to targeted modulation of glutamate transmission in selected pathways. To reduce glutamatergic transmission, he created a transgenic mouse in which glutaminase, the enzyme most responsible for the production of glutamate, the main excitatory neurotransmitter in the brain, is reduced by about 50%. While regular mice show a moderate increase in activity in response to a psychosis-engendering drug (MK-801), the glutaminase mutants show an extremely dramatic increase in locomotion, and completely ignore the reality of risks of being out in the open. They are in effect genetically predisposed to psychotic-like behavior. Dr. Rayport hypothesizes that one particular glutamatergic pathway contributes most to this vulnerability and that he can identify this pathway by targeted restoration of glutaminase function. He will do a more extensive behavioral analysis of the glutaminase mutant mice as a new animal model for schizophrenia, validate the model by showing that glutaminase deficiency results in dopamine imbalance (as in schizophrenia), and rescue full glutaminase expression in specific pathways to identify the one or ones that underlie sensitivity to the psychosis-engendering drug (MK-801). If the primary lesion in schizophrenia involves the cortex, and in particular the cortical projections, then cortical rescue of full glutaminase function should normalize the MK-801-stimulated excessive center activity. Alternately, recent evidence indicates that dopaminergic neurons use glutamate as a co-transmitter. He will test the effect of restoring glutamatergic transmission in dopaminergic neurons and will restore thalamic glutamatergic projections to the cortex, as these projections have also been implicated in schizophrenia. Once he has identified crosses that eliminate the behavioral phenotype, he will do microdialysis to show that the dopamine imbalance has also been corrected. He hopes to identify the crucial glutamatergic pathways involved in the pathogenesis of schizophrenia.

Program Area: SCHIZOPHRENIA/PSYCHOTIC DISORDERS\Schizophrenia

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