Schizophrenia is a common, devastating illness, which most often leads to life long disability. Despite recent advances, the cellular and molecular pathophysiology of this illness remains unknown. In this mentored career development award, the candidate will test the general hypothesis that projection neurons in the mediodorsal thalamic nucleus (MDTN) are abnormal in schizophrenia, and that this abnormality is associated with alterations in the pattern of gene expression in the MDTN. Recent postmortem studies have reported that the MDTN is smaller in size and has fewer neurons and glial cells in subjects with schizophrenia compared to normal subjects. The results of these studies have raised the following questions that will be addressed in the proposed studies: 1) Is a decrease in neuronal number and volume of the MDTN common in schizophrenia, and is it diagnostically specific to the illness? 2) Which neuronal subpopulations are affected- local circuit neurons or neurons that project to the prefrontal cortex? 3) What alterations in MDTN gene expression are associated with, and potentially causal to these abnormalities? 4) Are these findings part of the pathophysiology of the illness or are they the result of chronic treatment with antipsychotic medications? While investigating these questions, the candidate, a child psychiatrist, will under take a program of study to develop skills in 1) the conduct of rigorous human postmortem studies, 2) the techniques of stereology, immunohistochemistry, and in situ hybridization, and 3) the analysis of patterns of tissue specific gene expression in psychiatric disease. Finally, he will learn how to use a nonhuman primate model of clinical phenomena to understand human disease and treatment. Acquiring these skills at the University of Pittsburgh, under the mentorship of Professors David A. Lewis and Pat R. Levitt, will enable the candidate to launch a career investigating the developmental pathophysiology of psychiatric disorders which have their onset in childhood and adolescence.
