MOLECULAR NEUROBIOLOGY OF SCHIZOPHRENIA

Requested is a Physician Scientist Award to study the molecular neurobiology of schizophrenia. Schizophrenia, is a serious and common psychiatric syndrome of unknown etiology; on the basis of population genetics studies it appears to be heritable, but no candidates for the hypothesized abnormal gene (or genes) have emerged. Pharmacologic studies suggest a role for increased dopamine neurotransmission in the pathogenesis of schizophrenia while postmortem studies suggest that enhanced dopamine activity may result from increased concentrations of post-synaptic dopamine-2 receptors (D-2) in mesolimbic pathways. The research project proposes a molecular genetic examination of the hypothesis that abnormalities in coding or regulatory regions of the D-2 gene contribute to the etiology of schizophrenia. The project consists of three phases: 1) Obtaining a cloned cDNA probe to D-2 mRNA (by means of two novel cloning strategies, the first involving receptor protein expression in the bacteriophage, lambda gtll, followed by radioligand screening; the second combining differential hybridization, gene transfection, translation arrest, and electrophysiological monitoring of expression). 2) Using this probe to quantitate D-2 mRNA in mesolimbic nucleic of frozen postmortem material from schizophrenic patients and matched controls and of neuroleptic-treated and -naive rats (employing both solution and in situ hybridization techniques and permitting an assessment of the relative roles of transcription and translation and of disease and of disease and drug in receptor binding abnormalities that have been observed). 3) Applying the probe in a linkage analysis of schizophrenia in a northern Swedish geographical isolate and, should linkage be established, in a second American population. In the course of this project, broad training will be received in two fields, molecular neurobiology and population genetics, training that will permit further study of the molecular genetic lesions in schizophrenia, whether or not these lesions are associated with abnormalities in D-2 expression.