Project Summary

Diego Restrepo, Ph.D. (Distinguished Investigator 2005) of University of Colorado Health Sciences Center, notes that modern human genetics, molecular biology and functional imaging have allowed unprecedented advances in our understanding of the neural basis of schizophrenia. Thus, it is clear that this disease has both genetic and environmental causes, and mutations in several genes including the alpha 7 acetylcholine receptor gene (CHRNA7) have been implicated in schizophrenia. Although the identification of these mutations as potential factors contributing to schizophrenia is exciting, and could lead to development of new therapies, a major obstacle is the inability to determine the nature of functional changes of human neurons in schizophrenics compared to controls. Along with two other groups, Dr. Restrepo can culture human olfactory bulb neurons from cadavers from genotyped schizophrenics and controls allowing him, for the first time, to study function in neurons from schizophrenics. Building on his success culturing olfactory receptor neurons in the past, Dr. Restrepo now proposes cultures of olfactory bulb from adult rodents and humans, as model systems for the study of alterations in cellular physiology associated with genetically determined changes in a7 nicotinic receptor expression. He has targeted the study of the functional consequences of this mutation because his collaborators have identified CHRNA7 as one of the loci for mutations contributing to schizophrenia, and because these investigators have agreed to collaborate with him and provide genotyped cadaver samples of human olfactory bulb. Interestingly, although first attracted to this line of research because of the alpha7 work, he notes that dysbindin and neuregulin, two of the other genes that appear to be involved in schizophrenia are also involved in synapse formation and specifically in the formation of nicotinic synapses. Thus, his work could be extended to understand the functional role of these two other genes in neuronal dysfunction in schizophrenia.

Program Area: SCHIZOPHRENIA/PSYCHOTIC DISORDERS\Schizophrenia

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