Neuron Subtype and Circuit Specific Patterns of Gene Expression in Schizophrenia

University Of Alabama At Birmingham, Birmingham AL

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Abstract

DESCRIPTION (provided by applicant): This application is in response to NIMH Challenge Area (08) Genomics, Challenge Topic 08-MH-102, Schizophrenia Interactome. Schizophrenia is a devastating mental illness affecting millions in the US and worldwide, with profound human and economic costs. While there are treatments for this illness that ameliorate some of the symptoms, there is no cure and the medications currently in use often have significant unwanted side effects. Thus, there is tremendous need for new approaches for the diagnosis and treatment of this illness. Over the past few years, a number of novel gene products and pathways have been identified pointing to a higher level of complexity of the cell biology of neurotransmission, resulting in numerous candidate genes for involvement in the pathophysiology of schizophrenia. In addition, a number of investigators consider schizophrenia a disorder of limbic circuitry, and while methods to study circuit- based abnormalities in this illness have been developed and validated, many projects have not realized the full potential of these tools. We propose to measure in brains of persons that had schizophrenia and a comparison group the expression of ~100 candidate genes associated with neurotransmission that have previously been identified in gene array and other studies using postmortem brain material. We will use laser capture microscopy (LCM) to harvest individual neurons from multiple interconnected brain regions, thus measuring expression of these candidate genes in defined neuronal subpopulations within the context of the cortico-striato-thalamic circuitry hypothesized to be a substrate for many features of the pathophysiology of this illness. This challenge area meets several critical needs. Scientifically, it provides a rare opportunity to determine the molecular genetic fingerprint of patterns of gene expression of an exciting set of neurotransmitter-related candidate genes in defined neuronal populations with brain regions associated with limbic circuitry. These data would permit the testing of hypotheses of abnormalities in schizophrenia of expression of these genes in specific subsets of neurons and within limbic circuits. In addition, this work is labor-intensive and facilitates creation of new employment opportunities for a defined period during this time of economic recovery. The University of Alabama at Birmingham (UAB) is Alabama's largest employer, with more than 18,000 faculty and staff at the university and in the health system, and is responsible for 52,900 full-time equivalent jobs within the university and the community. Eight in every 100 jobs in the Birmingham area, and 2.8 jobs in every 100 jobs in Alabama, are related to UAB. UAB's overall economic impact in the Birmingham metro area exceeds $3 billion annually. Consistent with ARRA goals, this application will create or retain four full time and one part time job. PUBLIC HEALTH RELEVANCE: This project will identify the critical elements of brain function that contribute to the pathophysiology of schizophrenia. Identification of the molecular elements underlying schizophrenia will provide new targets for the development of medicines to treat this illness.